"Too Fat" Part Four!...

margd: Hulled barley is SO-O much more substantial than pearled barley. Takes much longer to cook. Next-day soup is thick like a stew! Couldn't find hulled barley locally though, so amazon.

Less snacking, more satisfaction: Some foods boost levels of an Ozempic-like hormone
Michaeleen Doucleff | October 30, 2023

...a fiber in barley, called beta-glucan, induced the most weight loss in obese animals. "At face value and, at least in our settings, it was only beta-glucan that was effective," he says.

...Beta-glucan is also found in oats and rye. And indeed, studies with people have found that beta-glucan fiber may improve insulin sensitivity, lower blood pressure and increase satiation between meals.

Other fermentable fibers include dextrin in wheat, oligosaccharides in beans, peas and lentils, and pectin in apples, pears and green bananas...

...How To Add Barley To Your Diet
Cooking barley is super easy. Some recipes call for soaking the grain before boiling. But it's not necessary. Simply add one cup of barley and three cups of water to a pot.
For pearled barley, continue boiling for about 30 minutes. For hulled barley, boil for about 40 minutes. Strain the water and you're ready!
You can throw barley into soups or on salads and boiled barley is a great fiber-rich substitute for white rice. You can also buy barley flour and use it for baking breads, muffins and pancakes.

https://www.npr.org/sections/health-shots/2023/10/30/1208883691/diet-ozempic-weg...

Lars T Fadnes et al. 2023. Life expectancy can increase by up to 10 years following sustained shifts towards healthier diets in the United Kingdom. Nature Food volume 4, pages 961–965 (20 Nov 2023). Open access. https://www.nature.com/articles/s43016-023-00868-w
Abstract

Adherence to healthy dietary patterns can prevent the development of non-communicable diseases and affect life expectancy. Here, using a prospective population-based cohort data from the UK Biobank, we show that sustained dietary change from unhealthy dietary patterns to the Eatwell Guide dietary recommendations is associated with 8.9 and 8.6 years gain in life expectancy for 40-year-old males and females, respectively. In the same population, sustained dietary change from unhealthy to longevity-associated dietary patterns is associated with 10.8 and 10.4 years gain in life expectancy in males and females, respectively. The largest gains are obtained from consuming more whole grains, nuts and fruits and less sugar-sweetened beverages and processed meats. Understanding the contribution of sustained dietary changes to life expectancy can provide guidance for the development of health policies.

Eric Topol (Scripps) @EricTopol | 11:07 AM · Dec 7, 2023:

The amazing GLP-1 drugs are associated with reduced risk of colon cancer, even in people with #T2D who are not overweight, during 15-year follow-up

Lindsey Wang et al. 2023. GLP-1 Receptor Agonists and Colorectal Cancer Risk in Drug-Naive Patients With Type 2 Diabetes, With and Without Overweight/Obesity (Research Letter) JAMA Oncol. Published online December 7, 2023. doi:10.1001/jamaoncol.2023.5573 https://jamanetwork.com/journals/jamaoncology/fullarticle/2812769

A new Science Translational Medicine Review looks at the decades of basic research and scientific breakthroughs that led to the discovery of semaglutide (Ozempic) and similar drugs, which are transforming obesity into a treatable disease.

Matthias H. Tschöp and Jeffrey M. Friedman 2023. Seeking satiety: From signals to solutions (Review). Science Translational Medicine 22 Nov 2023. Vol 15, Issue 723.
DOI: 10.1126/scitranslmed.adh4453 https://www.science.org/doi/10.1126/scitranslmed.adh4453

Abstract
Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to “reduce food and avoid drinking to fullness” and begin “running during the night.” Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed that may soon enable physicians to manage body weight in patients with obesity in a manner similar to the way that blood pressure is controlled in patients with hypertension. These medicines have grown out of a revolution in our understanding of the molecular and neural control of appetite and body weight, reviewed here.

https://twitter.com/EricTopol/status/1735374864448667795/photo/1

Eric Topol (Scripps MD-scientist) @EricTopol | 2:03 PM · Dec 14, 2023:

H. Holden Thorp* 2023. More questions than answers (Editorial). Science
14 Dec 2023. Vol 382, Issue 6676, p. 1213. DOI: 10.1126/science.adn3693
https://science.org/doi/10.1126/science.adn3693

Text, highlighted ( https://twitter.com/EricTopol/status/1735374864448667795/photo/1 )

...GLP-1 agonists have been around since 2005 to treat type 2 diabetes and were approved for weight loss as early as 2014. But it was only since 2021, when the GLP-1 drug semaglutide was approved (as Wegovy) for obesity (it is sold as Ozempic for diabetes), that the frenzy really began, and mainstream media started referring to them as “the medical sensation of the decade.”

...GLP-1 agonists have raised more questions than they have answered—a hallmark of a true breakthrough. The first is about their cost and availability...

...Other questions relate to the need to stay on the drugs indefinitely to avoid regaining weight. A major assumption is that these are lifetime drugs. Are there safety implications associated with long-term use? How will clinicians decide how much weight loss justifies lifetime use of the drug? And at what age? These concerns become more pronounced for younger patients who will be on the drug for longer...

...Old pejorative tropes about obesity being the result of low willpower were hurtful to begin with, but now there is compelling evidence that a biochemical difference, not mental weakness, is responsible for weight gain. Reduced appetite and reduced “food noise” are clear benefits of these drugs. Scientists will over time refine our understanding of the genetic and environmental factors involved with body mass. That might lower the stigma and judgment around weight.

And that would truly be a breakthrough.

https://www.science.org/doi/10.1126/science.adn3693

* Dr. Thorp became Editor-in-Chief of the Science family of journals on 28 October 2019. He came to Science from Washington University, where he was provost from 2013 to 2019 and where he is Rita Levi-Montalcini Distinguished University Professor and holds appointments in both chemistry and medicine. He joined Washington University after spending three decades at the University of North Carolina at Chapel Hill (UNC), where he served as the 10th chancellor from 2008 through 2013.
https://www.science.org/content/author/holden-thorp-phd

>5 margd:, contd.

2023 Breakthrough of the Year: GLP-1 drugs
14 Dec 2023.

A version of this story appeared in Science, Vol 382, Issue 6676:
Obesity meets its match

Obesity plays out as a private struggle and a public health crisis. In the United States, about 70% of adults are affected by excess weight, and in Europe that number is more than half. The stigma against fat can be crushing; its risks, life-threatening. Defined as a body mass index of at least 30, obesity is thought to power type 2 diabetes, heart disease, arthritis, fatty liver disease, and certain cancers.

Yet drug treatments for obesity have a sorry past, one often intertwined with social pressure to lose weight and the widespread belief that excess weight reflects weak willpower. From “rainbow diet pills” packed with amphetamines and diuretics that were marketed to women beginning in the 1940s, to the 1990s rise and fall of fen-phen, which triggered catastrophic heart and lung conditions, history is beset by failures to find safe, successful weight loss drugs.

But now, a new class of therapies is breaking the mold, and there’s a groundswell of hope that they may dent rates of obesity and interlinked chronic diseases. The drugs mimic a gut hormone called glucagon-like peptide-1 (GLP-1), and they are reshaping medicine, popular culture, and even global stock markets in ways both electrifying and discomfiting. Originally developed for diabetes, these GLP-1 receptor agonists induce significant weight loss, with mostly manageable side effects. This year, clinical trials found that they also cut symptoms of heart failure and the risk of heart attacks and strokes, the most compelling evidence yet that the drugs have major benefits beyond weight loss itself. For these reasons, Science has named GLP-1 drugs the Breakthrough of the Year. Read the full story...

https://www.science.org/content/article/breakthrough-of-the-year-2023

When one twin goes vegan and the other doesn’t
Kenny Torrella@KennyTorrella | Jan 12, 2024

...Published in the medical journal JAMA Network Open* in November, the first-of-its-kind study recruited 22 pairs of identical twins, split up by diet. In each twin pair, one was randomly assigned to eat a healthy vegan diet for eight weeks while the other was assigned a healthy omnivore diet that included meat, eggs, and dairy. Those in the vegan cohort ended the study with much better health outcomes, particularly lower fasting insulin and lower cholesterol — a key indicator for heart health.

While most nutrition research is published with little fanfare, the twin study has received outsize attention thanks to an accompanying Netflix documentary series — You Are What You Eat: A Twin Experiment — that follows the culinary journeys of four of the twin pairs participating in the study. It was released in early January — right in time for New Year’s resolutions — and quickly became one of the streaming platform’s most watched television programs in the US...

https://www.vox.com/future-perfect/24034578/vegan-twin-study-stanford-you-are-wh...
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You Are What You Eat: A Twin Experiment | Official Trailer | Netflix (2:18)

Identical twins change their diets and lifestyles for eight weeks in a unique scientific experiment designed to explore how certain foods impact the body.

https://www.youtube.com/watch?v=oygkWmXyOaM
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Matthew J. Landry et al. 2023. Cardiometabolic Effects of Omnivorous vs Vegan Diets in Identical TwinsA Randomized Clinical Trial. JAMA Netw Open. 30 Nov 2023; 6(11):e2344457. doi:10.1001/jamanetworkopen.2023.44457 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2812392?resultClick...

Abstract
...Results. A total of 22 pairs (N = 44) of twins (34 {77.3%} female; mean...age, 39.6 ... years; mean ... body mass index, 25.9 ...) were enrolled in the study. After 8 weeks, compared with twins randomized to an omnivorous diet...
decreases in low-dens; 95% CI, −5.3 to −0.4 μIU/mL), and
body weight (−1.9 ... kg...).

Conclusions and Relevance In this randomized clinical trial of the cardiometabolic effects of omnivorous vs vegan diets in identical twins, the healthy vegan diet led to improved cardiometabolic outcomes compared with a healthy omnivorous diet. Clinicians can consider this dietary approach as a healthy alternative for their patients.

...Discussion
In this randomized clinical trial of healthy, adult identical twins, the 8-week change in LDL-C level—the primary outcome—was significantly lower for twins receiving the vegan diet compared with twins receiving the omnivorous diet. Insulin levels and weight were also significantly lower among the twins on the vegan diet from baseline to 8 weeks. Vegan-diet participants had total lower protein intake as a percentage of calories, lower dietary satisfaction, lower intake of dietary cholesterol, but higher intake of vegetable servings and intake of dietary iron. Vegans had lower intake of vitamin B12, yet serum vitamin B12 levels were not statistically different than omnivores at 8 weeks, likely because of preserved stores... Long-term vegans are typically encouraged to take a cyanocobalamin (vitamin B12) supplement.

...Two factors may have limited our opportunity to observe additional differences between the study groups. First, participants in both diet groups were assigned to eat a healthy diet...omnivorous participants improved their diet quality during the 8-week intervention (eg, increased vegetables and whole grain intake and decreased added sugars and refined grains). Second,...participants were healthy at baseline. For example, participants’ mean baseline LDL-C level was 114 mg/dL,26 leaving minimal room for participants to improve through diet alone. Nonetheless, we observed significant improvements in 3 clinical outcomes (LDL-C, insulin, and weight) among the vegan participants.

Our results corroborate a previous finding showing that eating a vegan diet can improve cardiovascular health...

We were surprised that TMAO concentrations did not significantly differ between diets at 8 weeks because of the higher meat content in the omnivorous diet and of the meat TMAO precursors choline and carnitine...In a sensitivity analysis that removed 3 TMAO outlier participants, lower TMAO levels were found in the vegan participants...In addition to our 3 TMAO outliers, we observed variability among participants in TMAO concentration changes...

...Although our findings suggest that vegan diets offer a protective cardiometabolic advantage compared with a healthy, omnivorous diet, excluding all meats and/or dairy products may not be necessary because research... suggests that cardiovascular benefits can be achieved with modest reductions in animal foods and increases in healthy plant-based foods compared with typical diets. We believe lower dietary satisfaction in the vegan group may have been attributable to the strictness of the vegan diet, creating more barriers for people to follow the vegan diet guidelines. Some people may find a less restrictive diet preferable for LDL-C–lowering effects. Future studies assessing health benefits of less strict plant-based diets will be necessary to assess these benefits, especially in a study model limiting additional biases (eg, in twins)...

Conclusions
In this randomized clinical trial, we observed cardiometabolic advantages for the healthy vegan vs the healthy omnivorous diet among healthy, adult identical twins. Clinicians may consider recommending plant-based diets to reduce cardiometabolic risk factors, as well as aligning with environmental benefits.

pp 10-15 How the Female Body Drove 200 Million Years of Human Evolution by Cat Bohannon

Fat is an organ system. Each fat deposit on our body is a little bit different, but women's hip, buttock, an upper thigh fat or "gluteofemoral" fat is chockful of longchain PUFAs (think omega-3, fish oil) --> baby brains and retinas. Gluteofemoral fat resists being metabolized until the last trimester of pregnancy throughout the first year of breastfeeding. Human pregnancy sucks, and our bodies have evolved ways to help us survive it.

After liposuction of gluteofemral fat, a different kind of fat accumulates on women's underarms.

Adipose tissue and our livers and our immune systems all came from the same primordial organ, called the "fat body"--all three regenerate tissue, hormonal signaling, deep responsiveness to shifts in local environments...

Nicotine's surprising effect on gut microbiota and metabolism uncovered
Dr. Priyom Bose, Ph.D. | .Jan 15 2024

...Study findings
The current study reflects the intense interplay of the gut microbiota and their metabolites and host metabolic characteristics in the backdrop of nicotine exposure.

Intraperitoneal nicotine administration was found to have a profound effect on weight regulation and metabolic phenotypes. This effect was independent of reduced caloric intake.

Mechanistically, the nicotine-induced body weight suppression was modulated by specific gut bacteria, including Lactobacillus spp, synthesizing KetoB (linoleic acid) during HFD {high fat diets} intake alone.

Several studies have shown that nicotine decreases body weight and food intake via the hypothalamic melanocortin system.

A decrease in the relative abundance of Lactobacillus spp. occurred in response to high HFD exposure. This bacterial population spiked in the presence of nicotine, particularly under HFD conditions.

The pair-feeding model in this study indicated that the main mechanism of weight control induced by nicotine administration was linked to decreased caloric intake. No specific correlation was observed between caloric intake and body weight even under ad libitum conditions.

Although nicotine administration resulted in a reduction in caloric intake in both ND {normal diet} and HFD groups, a greater reduction in body weight specifically occurred in the HFD group.

This result indicates that diet-dependent factors contribute to weight loss triggered by nicotine treatment. An elevated concentration of LCFAs that impacted gut microbial sensitivity to nicotine was found in the HFD group.

The increase in plasma non-esterified fatty acid (NEFA) after intraperitoneal nicotine administration in HFD-fed mice indicates the role of nicotine in promoting lipolysis.

The gut microbiota depletion model using antibiotic treatment in HFD-fed mice revealed that gut microbiota and their dietary fatty acid-derived metabolites are crucial in nicotine-induced body weight loss. The treated mice also significantly reduced caloric intake following nicotine administration.

Conclusions

The current study identified Keto B as a regulator of body weight loss associated with nicotine administration.

It highlighted the broad interplay of gut microbe in response to smoking that influences varied metabolic conditions including lowering of body weight.

Notably, the use of microbes in weight reduction has been reflected in this study.

https://www.news-medical.net/news/20240115/Nicotines-surprising-effect-on-gut-mi...
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Banno, Y., Masujima, Y., and Kimura, I. (2024) Gut microbial metabolites reveal diet-dependent metabolic changes induced by nicotine administration. Scientific Reports. 14(1), pp.1-11. doi:https://doi.org/10.1038/s41598-024-51528-3. https://www.nature.com/articles/s41598-024-51528-3

...Discussion
...In this study, we demonstrated that significant alterations in the gut microbiota following intraperitoneal nicotine administration were specifically observed under HFD {high fat diet}alone, suggesting that elevated concentrations of LCFAs {long chain fatty acids} resulting from HFD intake indicate a potential impact on sensitivity to nicotine through modulation of the gut environment. Furthermore, the differences in the nicotine administration protocol may contribute not only to the alteration of gut microbial composition but also to the modulation of their metabolite profiles. Direct nicotine exposure in the intestinal tract via oral administration can alter the gut microbiota through physicochemical changes, including increased intestinal pH... Conversely, nicotine intraperitoneal administration is considered to be absorbed into the systemic bloodstream and to indirectly affect the gut microbiota through nicotine receptors such as α7 nAChR, expressed in the central nervous system or enteric neural circuits... Indeed, our results revealed that intraperitoneal administration of nicotine resulted in an increase in the abundance of Firmicutes, whereas oral administration led to a decrease in Firmicutes and a concomitant increase in Bacteroidetes, in accordance with a previous report, consequently leading to an elevation in SCFA levels exclusively during oral administration. Further comprehensive investigations of the intricate regulatory mechanisms of the gut microbial community in response to nicotine exposure will provide insights into previously unknown mechanisms governing nicotine-induced host metabolic modulation.

Switching to vegan or ketogenic diet rapidly impacts immune system, study shows
NIH/National Institute of Allergy and Infectious Diseases |

...The vegan diet significantly impacted pathways linked to the innate immune system, including antiviral responses. On the other hand, the keto diet led to significant increases in biochemical and cellular processes linked to adaptive immunity, such as pathways associated with T and B cells.

The keto diet affected levels of more proteins in the blood plasma than the vegan diet, as well as proteins from a wider range of tissues, such as the blood, brain and bone marrow. The vegan diet promoted more red blood cell-linked pathways, including those involved in heme metabolism, which could be due to the higher iron content of this diet.{margd: counterintutitive to me, but checked and that's what study states.}

Additionally, both diets produced changes in the microbiomes of the participants, causing shifts in the abundance of gut bacterial species that previously had been linked to the diets. The keto diet was associated with changes in amino acid metabolism—an increase in human metabolic pathways for the production and degradation of amino acids and a reduction in microbial pathways for these processes—which might reflect the higher amounts of protein consumed by people on this diet.

...According to the authors, the results of this study demonstrate that the immune system responds surprisingly rapidly to nutritional interventions. The authors suggest that it may be possible to tailor diets to prevent disease or complement disease treatments, such as by slowing processes associated with cancer or neurodegenerative disorders.

https://medicalxpress.com/news/2024-01-vegan-ketogenic-diet-rapidly-impacts.html
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Verena M. Link et al. 2024. Differential peripheral immune signatures elicited by vegan versus ketogenic diets in humans. Nature Medicine (30 January 2024) DOI: 10.1038/s41591-023-02761-2 https://www.nature.com/articles/s41591-023-02761-2

Open access

Abstract
...Our data revealed that overall, a ketogenic diet was associated with a significant upregulation of pathways and enrichment in cells associated with the adaptive immune system. In contrast, a vegan diet had a significant impact on the innate immune system, including upregulation of pathways associated with antiviral immunity. Both diets significantly and differentially impacted the microbiome and host-associated amino acid metabolism, with a strong downregulation of most microbial pathways following ketogenic diet compared with baseline and vegan diet. Despite the diversity of participants, we also observed a tightly connected network between datasets driven by compounds associated with amino acids, lipids and the immune system. Collectively, this work demonstrates that in diverse participants 2 weeks of controlled dietary intervention is sufficient to significantly and divergently impact host immunity, which could have implications for precision nutritional interventions...

David J A Jenkins et al. 2024. Association of glycaemic index and glycaemic load with type 2 diabetes, cardiovascular disease, cancer, and all-cause mortality: a meta-analysis of mega cohorts of more than 100 000 participants. The Lancet Diabetes & Endocrinology, Volume 12, ISSUE 2, P107-118, February 2024. DOI:https://doi.org/10.1016/S2213-8587(23)00344-3 https://www.thelancet.com/journals/landia/article/PIIS2213-8587(23)00344-3/fullt...

Summary
Background
There is debate over whether the glycaemic index of foods relates to chronic disease. We aimed to assess the associations between glycaemic index (GI) and glycaemic load (GL) and type 2 diabetes, cardiovascular disease, diabetes-related cancers, and all-cause mortality.

Methods
...meta-analysis of large cohorts ...Primary outcomes were incident type 2 diabetes, total cardiovascular disease (including mortality), diabetes-related cancers (ie, bladder, breast, colorectal, endometrial, hepatic, pancreatic, and non-Hodgkin lymphoma), and all-cause mortality. We assessed comparisons between the lowest and highest quantiles of GI and GL, adjusting for dietary factors, and pooling their most adjusted relative risk (RR) estimates using a fixed-effects model. We also assessed associations between diets high in fibre and whole grains and the four main outcomes...

Findings
...Consumption of high GI foods was associated with an increased incidence of type 2 diabetes (RR 1·27 ...), total cardiovascular disease (1·15 ...), diabetes-related cancer (1·05 ...), and all-cause mortality (1·08 ...). Similar associations were seen between high GL and diabetes (RR 1·15...) and total cardiovascular disease (1·15 ...). Associations between diets high in fibre and whole grains and the four main outcomes were similar to those for low GI diets.

Interpretation
Dietary recommendations to reduce GI and GL could have effects on health outcomes that are similar to outcomes of recommendations to increase intake of fibre and whole grain.

Obesity can disrupt mitochondrial functions in the body, study finds
Corrie Pelc | January 29, 2024

...A new study found evidence that shows how obesity affects the body on a metabolic level by disrupting mitochondrial function. The results could potentially pave the way for new obesity treatments and prevention strategies...

...Using a mouse model, (lead study author Dr. Alan Saltiel, professor in the Department of Medicine at the University of California — San Diego School of Medicine)... and his team found when mice were fed a high fat diet, the mitochondria — known as the “powerhouse of the cell” — within fat cells fragmented into smaller mitochondria. Researchers found these smaller mitochondria could not burn as much fat as when the larger mitochondria were all together.

“In the normal, non-obese state, mitochondria maintain their health through a cycle of continual fusion and fission, which means they break apart and reform,” Dr. Saltiel explained. “We found that the changes that occur in obesity tip the scales so that mitochondria break apart more — the process known as fission.”

The researchers also discovered that these changes only occur in one type of fat cells — the kind found below the skin (subcutaneous) that is mainly in the hips and thighs.

“This is thought to be the good adipose depot, as it has the potential to burn as well as store fat,” Dr. Saltiel said.

“We found that mitochondria are normally longer and more active in this fat depot compared to the adipose tissue found in the midsection — called visceral fat — but obesity causes excessive mitochondrial fission in subcutaneous fat, so it looks more like visceral fat and loses its ability to burn fat,” he noted.

...this fragmentation of mitochondria was caused by a single molecule called RaIA...

https://www.medicalnewstoday.com/articles/obesity-caused-by-metabolism-disruptin...
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Wenmin Xia et al. 2024. Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation. nature metabolism. Published: 29 January 2024. https://www.nature.com/articles/s42255-024-00978-0

Abstract
...chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

Nan Zhang et al. 2024. Dosage exploration of combined B-vitamin supplementation in stroke prevention: a meta-analysis and systematic review. American Journal of Clinical Nutrition. 1 Feb 2024. DOI:https://doi.org/10.1016/j.ajcnut.2023.12.021 https://ajcn.nutrition.org/article/S0002-9165(23)66354-3/fulltext

ABSTRACT
...Conclusion.
Our meta-analysis found that the folic acid combined with vitamin B12 and vitamin B6 supplementation strategy significantly reduced the risk of stroke in areas without and with partial folic acid fortification...

Cambridge Scientists Uncover New Way in Which Fasting Helps Reduce Inflammation
University of Cambridge | February 12, 2024

...Professor Clare Bryant from the Department of Medicine at the University of Cambridge said: “We’re very interested in trying to understand the causes of chronic inflammation in the context of many human diseases, and in particular the role of the inflammasome...What’s become apparent over recent years is that one inflammasome in particular – the NLRP3 inflammasome – is very important in a number of major diseases such as obesity and atherosclerosis, but also in diseases like Alzheimer’s and Parkinson’s disease, many of the diseases of older age people, particularly in the Western world.”

Fasting can help reduce inflammation, but the reason why has not been clear. To help answer this question, a team ... University of Cambridge and the National Institute for Health in the USA studied blood samples from a group of 21 volunteers, who ate a 500kcal meal and then fasted for 24 hours before consuming a second 500kcal meal.

...found that restricting calorie intake increased levels of a lipid known as arachidonic acid. Lipids are molecules that play important roles in our bodies, such as storing energy and transmitting information between cells. As soon as individuals ate a meal again, levels of arachidonic acid dropped.

When the researchers studied arachidonic acid’s effect in immune cells cultured in the lab, they found that it turns down the activity of the NLRP3 inflammasome. This surprised the team as arachidonic acid was previously thought to be linked with increased levels of inflammation, not decreased.

Professor Bryant, a Fellow of Queens’ College, Cambridge, added: “This provides a potential explanation for how changing our diet – in particular by fasting – protects us from inflammation, especially the damaging form that underpins many diseases related to a Western high-calorie diet...It’s too early to say whether fasting protects against diseases like Alzheimer’s and Parkinson’s disease as the effects of arachidonic acid are only short-lived..."

https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00028-7
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Milton Pereira et al. 2024. Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting. Cell Reports, 23 January 2024, .
DOI: 10.1016/j.celrep.2024.113700 https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00028-7

Fasting-like diet may help reverse biological aging by 2.5 years
Kaitlin Vogel | February 21, 2024

Fasting mimicking diet cycles versus a Mediterranean diet and cardiometabolic risk in overweight and obese hypertensive subjects: a randomized clinical trial

A study showed a fasting-mimicking diet (FMD) lowered insulin resistance, liver fat, inflammation, and other markers associated with aging.

The diet is based on the consumption of formulated food with controlled levels of dietary macros on days 1–5 and then eating normally for 25 days out of a month.

This fasting-like diet style is not suitable for everyone, including pregnant people and older adults...

https://www.medicalnewstoday.com/articles/fasting-like-diet-may-help-reverse-bio...
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Amrendra Mishra et al. 2023. Fasting mimicking diet {FMD} cycles versus a Mediterranean diet (MD) and cardiometabolic risk in overweight and obese hypertensive subjects: a randomized clinical trial. npj Metabolic Health and Disease volume 1, Article number: 1 (2023) https://www.nature.com/articles/s44324-023-00002-1

Abstract
... In summary, both MD and FMD reduced a range of cardiometabolic risk factors, but FMD also decreased RHI, a change associated with either impaired functional integrity of vascular endothelial cells but also with vascular rejuvenation, with the latter being more likely considering the improved cardiometabolic profile, reduced PULS cardiac score and calculated heart age, and unaltered arterial compliance in the FMD group. MD but not FMD cycles caused loss of lean body mass.

...Discussion
...These findings indicate that both interventions can effectively contribute to weight management and improve cardiometabolic disease risk (Fig. 2). Notably, only the FMD intervention showed a significant decrease in trunk fat mass, suggesting a potential advantage in targeting abdominal fat reduction.

Sarcopenia or the loss of lean muscle mass is associated with aging49. Notably, while the FMD group showed no change in lean muscle mass, the MD group showed nearly 5 lb loss of FFM and over 2 lb loss of leg muscle mass at the end of the follow-up period, which could contribute to increased frailty, falls and fractures in old age50.

Scientists find genes can raise obesity risk 'by six times'
Nina Massey, PA & Steven Smith | 4 April 2024

...the discovery of rare variants in the BSN and APBA1 genes are some of the first obesity-related genes identified for which the increased risk is not observed until adulthood.

https://www.msn.com/en-gb/health/other/ar-BB1l3FOd
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Yajie Zhao et al. 2024. Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease. Nature Genetics, 4 April 2024. OPEN ACCESS. https://www.nature.com/articles/s41588-024-01694-x

Abstract
Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

...Discussion
We found that rare PTVs in APBA1 and BSN were associated with a substantial increase in adult BMI and higher risks of obesity and severe obesity in adults. {Type 2 diabetes and Rare PTVs in BSN were also associated with higher risks for T2D and nonalcoholic fatty liver disease...APBA1 and BSN appear to be among the few genetic determinants of predominantly adult-onset obesity.

...we posit that adult obesity could result from some form of subtle age-dependent degeneration in primary appetitive regulatory pathways.

...we posit that adult obesity could result from some form of subtle age-dependent degeneration in primary appetitive regulatory pathways...as the common genetic susceptibility to obesity is thought to act predominantly via central regulation of food intake9,38, we hypothesize that BSN may have widespread involvement in neurodevelopment and neurogenesis, with BSN variants leading to increased appetitive drive.

...In conclusion, rare genetic disruptions of APBA1 and BSN have larger impacts on adult BMI and obesity risk than heterozygous disruptions of any previously described obesity risk gene. Rare PTVs in APBA1 and BSN appear to preferentially confer risk of adult-onset obesity, which we propose might be due to widespread dysregulation of neurodevelopment, neurogenesis and neuronal oxidative phosphorylation in neurons within the central feeding circuitry.

Mouse study shows how a father's diet can shape the health of his offspring
U of Sydney | 17 April 2024

...At the University of Sydney's Charles Perkins Center in Australia researchers fed male mice one of ten diets differing in the proportions of protein, fats, and carbohydrates, then allowed them to mate with females reared on standard diet. The behavior and physiology of the resulting pups were then studied.
The scientists discovered that male mice fed low protein and high carbohydrate diets were more likely to have male offspring with higher levels of anxiety, as measured by time spent in the safety zones of their maze. They also found that male mice that were fed high fat diets were more likely to have daughters with higher levels of body fat and markers of metabolic disease...

https://medicalxpress.com/news/2024-04-mouse-father-diet-health-offspring.html
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Angela Jane Cream et al. 2024. Paternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring. Nature Communications volume 15, Article number: 2982 (6 April 2024). https://www.nature.com/articles/s41467-024-46782-y
Abstract

Paternal diet can influence the phenotype of the next generation, yet, the dietary components inducing specific responses in the offspring are not identified. Here, we use the Nutritional Geometry Framework to determine the effects of pre-conception paternal dietary macronutrient balance on offspring metabolic and behavioral traits in mice. Ten isocaloric diets varying in the relative proportion of protein, fats, and carbohydrates are fed to male mice prior to mating. Dams and offspring are fed standard chow and never exposed to treatment diets. Body fat in female offspring is positively associated with the paternal consumption of fat, while in male offspring, an anxiety-like phenotype is associated to paternal diets low in protein and high in carbohydrates. Our study uncovers that the nature and the magnitude of paternal effects are driven by interactions between macronutrient balance and energy intake and are not solely the result of over- or undernutrition.

Discussion
...In conclusion, our study uncovered a dynamic interplay between preconceptional dietary composition and energy intake in paternal inheritance. Using the Nutritional Geometry Framework, we identified relationships between the consumption of certain macronutrients and offspring phenotypes in mice. Our mapping of offspring responses to complex paternal diets provides the foundations for future research directions in the development of preconceptional dietary guidelines for males.

Friday Favorites: The Role of Epigenetics in the Obesity Epidemic (5:33)
Michael Greger M.D. FACLM · April 19, 2024 ·

Astonishingly, a baby with a heavy surrogate mother and a thin biological mom may harbor a greater risk of becoming obese than a baby with a slim surrogate mom and a heavy biological one...

https://nutritionfacts.org/video/friday-favorites-the-role-of-epigenetics-in-the...

Sources cited:
Campbell MK. Biological, environmental, and social influences on childhood obesity. Pediatr Res. 2016;79(1-2):205-11.
Walton A, Hammond J. The maternal effects on growth and conformation in shire horse-shetland pony crosses. Proc R Soc B. 1938;125(840):311-35.
Brooks AA, Johnson MR, Steer PJ, Pawson ME, Abdalla HI. Birth weight: nature or nurture?. Early Hum Dev. 1995;42(1):29-35.
Waterland RA. Epigenetic mechanisms affecting regulation of energy balance: many questions, few answers. Annu Rev Nutr. 2014;34:337-55.
Smith J, Cianflone K, Biron S, et al. Effects of maternal surgical weight loss in mothers on intergenerational transmission of obesity. J Clin Endocrinol Metab. 2009;94(11):4275-83.
Wang Z, Wang Q, Liu Y. You are what your parents ate: a Darwinian perspective on the inheritance of food effects. Trends Food Sci Technol. 2016;54:204-7.
Mcallister EJ, Dhurandhar NV, Keith SW, et al. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr. 2009;49(10):868-913.
Finch CE, Loehlin JC. Environmental influences that may precede fertilization: a first examination of the prezygotic hypothesis from maternal age influences on twins. Behav Genet. 1998;28(2):101-6.
Keith SW, Redden DT, Katzmarzyk PT, et al. Putative contributors to the secular increase in obesity: exploring the roads less traveled. Int J Obes (Lond). 2006;30(11):1585-94.
Luque V, Closa-monasterolo R, Escribano J, Ferré N. Early Programming by Protein Intake: The Effect of Protein on Adiposity Development and the Growth and Functionality of Vital Organs. Nutr Metab Insights. 2015;8(Suppl 1):49-56.
Cope MB, Allison DB. White hat bias: examples of its presence in obesity research and a call for renewed commitment to faithfulness in research reporting. Int J Obes (Lond). 2010;34(1):84-8.
Horta BL, Bahl R, Martinés JC, Victora CG. Evidence on the long-term effects of breastfeeding: systematic reviews and meta-analysis. World Health Organization. 2007.
Katzmarzyk PT, Barlow S, Bouchard C, et al. An evolving scientific basis for the prevention and treatment of pediatric obesity. Int J Obes (Lond). 2014;38(7):887-905.

A woman couldn't understand why she wasn't losing weight after trying diets, exercise, and medication. A test revealed she was missing crucial gut microbes.
Kim Schewitz | May 9, 2024

...{Researchers} found that {Kimmie} Gilbert's microbial community was less diverse than those of people who were considered a healthy weight. One large 2008 study found that people with obesity tended to have similar microbiomes with low diversity.

A microbe called Prevotella, which is associated with weight loss, wasn't found at all in her gut. "People who have that pattern of no Prevotella have a hard time losing weight," {Annie Gupta, an assistant professor at UCLA and co-director of the Goodman-Luskin Microbiome Center} told the documentary. In a 2018 study based on 52 overweight people, those who had higher levels of Prevotella lost significantly more weight than those with low levels.

The researchers also found that she had low quantities of three other types of bacteria associated with a gut hormone that makes you feel full.

No bacteria acts alone, {Eran Segal, a computational biologist at the Weizmann Institute of Science} said: "They act within an ecosystem, which is why we analyze the microbiome as a whole."

The experts recommended Gilbert make an enjoyable but sustainable lifestyle change that would help her repopulate her gut with more "good" bacteria. Eating 20 to 30 fruits and vegetables a week is usually considered beneficial, Gupta said...

https://www.businessinsider.com/woman-couldnt-lose-weight-missing-crucial-gut-mi...
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"Hack Your Health: The Secrets of Your Gut"
In the Search for Wellness, Hack Your Health Goes Straight to the Gut
Roxanne Fequiere | April 29, 2024

In the new doc, four people undergo an experiment that may be … hard to digest.

In recent years, doctors and scientists have studied the gut with renewed interest. Research has revealed that the digestive system is more than just a processing center for the food we eat, and that it has a much bigger effect on our overall health than previously thought. Issues as varied as stubborn weight gain and Parkinson’s disease can be linked to the gut, which means that understanding our digestive system — and, by extension, how it thrives or suffers based on what we eat — is crucial. In a new documentary, "Hack Your Health: The Secrets of Your Gut", German doctor Giulia Enders partners with colleagues to explain how the gut works — and how to make it work for you...

https://www.netflix.com/tudum/articles/hack-your-health-secrets-of-your-gut-rele...
_________________________________

This looks like the 2018 Prevotella study behind the Netflix documentary? Previously posted in https://www.librarything.com/topic/269570#6180516 .

Mads F. Hjorth et al. 2018. Prevotella-to-Bacteroides ratio predicts body weight and fat loss success on 24-week diets varying in macronutrient composition and dietary fiber: results from a post-hoc analysis. (NATURE) International Journal of Obesity volume 43, pages 149–157 (2019). Published 17 May 2018. Open access.

Abstract
Background/objectives
Individuals with high pre-treatment bacterial Prevotella-to-Bacteroides (P/B) ratio have been reported to lose more body weight on diets high in fiber than subjects with a low P/B ratio. Therefore, the aim of the present study was to examine potential differences in dietary weight loss responses between participants with low and high P/B.

Subjects/methods
Eighty overweight participants were randomized (52 completed) to a 500 kcal/d energy deficit diet with a macronutrient composition of 30 energy percentage (E%) fat, 52 E% carbohydrate and 18 E% protein either high (≈1500 mg calcium/day) or low ( 600 mg or less calcium/day) in dairy products for 24 weeks. Body weight, body fat, and dietary intake (by 7-day dietary records) were determined. Individuals were dichotomized according to their pre-treatment P/B ratio derived from 16S rRNA gene sequencing of collected fecal samples to test the potential modification of dietary effects using linear mixed models.

Results
Independent of the randomized diets, individuals with high P/B lost 3.8 kg ... more body weight and 3.8 kg ... more body fat compared to individuals with low P/B. After adjustment for multiple covariates, individuals with high P/B ratio lost 8.3 kg ... more body weight when consuming above compared to below 30 g fiber/10MJ whereas this weight loss was 3.2 kg ... among individuals with low P/B ratio {Mean difference: 5.1 kg }. Partial correlation coefficients between fiber intake and weight change was 0.90 ... among individuals with high P/B ratio and 0.25 ... among individuals with low P/B ratio.

Conclusions
Individuals with high P/B lost more body weight and body fat compared to individuals with low P/B, confirming that individuals with a high P/B are more susceptible to weight loss on a diet rich in fiber.

Discussion (https://www.nature.com/articles/s41366-018-0093-2#Sec5)
... industrialized populations consuming a Western diet have microbiotas that are dominated by the family Bacteroidaceae (composed of four genera including Bacteroides) whereas traditional populations across Africa, Asia, and South America have microbiotas that are dominated by the family Prevotellaceae (composed of four genera including Prevotella) that has been found to fluctuate according to foods available during different seasons.... Although we know that it is difficult to change the P/B ratio though dietary interventions ... , we know that short term diets without carbohydrates ... and seasonal difference ... affect these genera and thereby provide evidence that we might be able to manipulate the P/B ratio.

In summary, we successfully validated the pre-treatment P/B ratio to be an important biomarker associated with dietary weight loss. Specifically, we found that participants having high P/B ratio had a larger 24 week weight loss compared to participants with low P/B ratio when advised to eat a healthy energy restricted diet (carbohydrate: 52E%, fat: 30 E% and protein: 18E%). This ≈4 kg differences in weight loss between high and low P/B ratio groups was explained by interaction with the actual diet consumed. Thus, individuals with a high P/B ratio were more susceptible to body weight loss, compared to individuals with a low P/B ratio, specifically on a diet rich in fiber and possibly also high in carbohydrates, high in protein and low in fat.

Study finds jaboticaba peel reduces inflammation and controls blood sugar in people with metabolic syndrome
FAPESP | 21 May 2024

...inflammation and blood sugar levels improved in volunteers with obesity and metabolic syndrome who took 15 g per day of powdered jaboticaba peel as a dietary supplement for five weeks.

....abnormally high level of blood sugar can lead to type 2 diabetes unless it is treated with medication and/or healthy habits and weight loss. "Jaboticaba peel supplement reduces the level of interleukin-6, which plays a key role in the development of insulin resistance and contributes to adipose tissue inflammation. Its positive effect on post-prandial blood sugar and inflammation makes it an ally for treatment of metabolic syndrome," he said.

More information: Marina Vilar Geraldi et al, Jaboticaba peel improves postprandial glucose and inflammation: A randomized controlled trial in adults with metabolic syndrome, Nutrition Research (2024). DOI: 10.1016/j.nutres.2024.02.008

https://medicalxpress.com/news/2024-05-jaboticaba-inflammation-blood-sugar-peopl...

Kombucha’s Microbial Magic: New Study Shows Fat-Busting Effects
PLOS | May 25, 2024

... more research is required to provide evidence that humans consuming kombucha experience similar effects as the C. elegans {nematode} model studied here—but these findings appear consistent with the reported human health benefits of kombucha ... and could inform the use of the beverage in complementary healthcare approaches in the future.

...“We were surprised to find that animals consuming a diet consisting of the probiotic microbes found in Kombucha Tea displayed reduced fat accumulation, lower triglyceride levels, and smaller lipid droplets – an organelle that stores the cell’s lipids – when compared to other diets. These findings suggest that the microbes in Kombucha Tea trigger a “fasting-like” state in the host even in the presence of sufficient nutrients.”...

https://scitechdaily.com/kombuchas-microbial-magic-new-study-shows-fat-busting-e...
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“Kombucha Tea-associated microbes remodel host metabolic pathways to suppress lipid accumulation” by Rachel N. DuMez-Kornegay, Lillian S. Baker, Alexis J. Morris, Whitney L. M. DeLoach and Robert H. Dowen, 28 March 2024, PLOS Genetics.
DOI: 10.1371/journal.pgen.1011003 https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1011003#s...

...Method...
...Kombucha brewing
Kombucha was brewed using a serial fermentation method adapted from a homebrewing Kombucha kit (The Kombucha Shop {https://www.thekombuchashop.com/}). Ultrapure water (1L) was boiled for 3 minutes, removed from the heat, and dried tea leaves (2.5 g of Assam Black Tea and 2.5 g Green Tea) were steeped for 5 minutes using an infuser. After removal of the tea infuser, 128 g of granulated cane sugar (Domino) was dissolved in the tea and the solution was poured into a clean 5L glass brewing jar before 3L of chilled ultrapure water was added. Once the solution cooled to below 30°C, the SCOBY and ~500 mL of the previous fermented Kombucha broth was added to the brew jar and a tight weave muslin cloth was affixed to the jar opening to limit contamination during fermentation. The jar was then placed in indirect sunlight at room temperature (between 24–28°C) and allowed to ferment for a minimum of 8 days before a new culture was started, which allowed for complete fermentation and a pH of ~4...

...Discussion
...we want to make it explicitly clear that we are not making judgements, conclusions or claims regarding Kombucha Tea’s use in any human medical practices or its recreational consumption. Our findings do, however, offer exciting insights into possible mechanisms of KT microbe-mediated host metabolic reprogramming and lays the foundation for future studies in mammalian model systems that could deconvolute the biological underpinnings of Kombucha Tea’s potential health benefits.

Study finds maternal obesity in mice increases microRNA levels in the hypothalamus in offspring, leading to overeating
Public Library of Science | June 4, 2024

...In this study, researchers found that mice born from obese mothers had higher levels of the microRNA miR-505-5p in their hypothalamus—from as early as the fetal stage into adulthood. The researchers found that the mice ate more and showed a preference for high-fat foods. Interestingly, the effect of maternal obesity on miR-505-5p and eating behaviors was mitigated if the mothers exercised during pregnancy.

Cell culture experiments showed that miR-505-5p expression could be induced by exposing hypothalamic neurons to long-chain fatty acids and insulin, which are both high in pregnancies complicated by obesity. The researchers identified miR-505-5p as a novel regulator of pathways involved in fatty acid uptake and metabolism, therefore, high levels of the miRNA make the offspring brain unable to sense when eating high fat foods.

Several of the genes that miR-505-5p regulates have been associated with high body mass index in human genetic studies. The study is one of the first to demonstrate the molecular mechanism linking nutritional exposure in utero to eating behavior."

"... the children of mothers living with obesity are more likely to become obese themselves, with early life exposures, genetics and current environment all being contributing factors."

More information: Dearden L, Furigo IC, Pantaleão LC, Wong LWP, Fernandez-Twinn DS, de Almeida-Faria J, et al. Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food. PLoS Biology (2024). DOI: 10.1371/journal.pbio.3002641

https://medicalxpress.com/news/2024-06-maternal-obesity-mice-microrna-hypothalam...

Researchers have found a ‘clear genetic trigger for obesity’ that applies to some people
Madeline Holcombe | June 20, 2024

... They compared data from people with two faulty copies of a particular gene (SMIM1) and those who did not have the two faulty copies.

Women with the gene mutation weighed an extra 4.6 kilograms (10.14 pounds), and men with the variant weighed an extra 2.4 kilograms (5.29 pounds), according to the study.

The faulty copies of the SMIM1 gene cause decreased function in the thyroid and declining energy expenditure, Frontini said, “which means that given the same food intake, less energy is used and this excess is stored as fat.” ...

https://www.cnn.com/2024/06/20/health/obesity-genetic-wellness/index.html
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Luca Stefanucci et al. 2024. SMIM1 absence is associated with reduced energy expenditure and excess weight. Med. Published:J une 20, 2024 DOI:https://doi.org/10.1016/j.medj.2024.05.015 https://www.cell.com/med/fulltext/S2666-6340(24)00219-8

Context and significance
Stefanucci et al. investigate the effects on human health of a 17-nucleotide deletion in the SMIM1 gene, known so far for encoding the antigen of the Vel blood group. In the article, the authors show, using large population cohorts, such as the UK Biobank, that the absence of SMIM1 is linked to excess weight, dyslipidemia, and related traits. The metabolic characterization of SMIM1−/− individuals points toward reduced energy expenditure as the main contributor to weight gain. Further research to understand the molecular mechanisms behind SMIM1-associated phenotypes might unlock new treatments for obesity and related conditions. This work highlights the importance of genetic and molecular insights in tackling metabolic disorders and improving public health...

...Discussion
... This variant is present in at least 200,000 individuals worldwide (1 in 5,000 individuals in Great Britain and higher frequency in the Scandinavian countries ... and extremely low frequency in other ancestries...

Because this review was presented to bariatric surgeons, take with grain of salt until published and peer-reviewed and available to read in the original. Not sure that it addresses all the benefits increasingly documented with GLP-1 agonists, e.g., alcohol can't/shouldn't be consumed w surgery, but some indication that GLP-1 agonists curb desire for alcohol(?):

New Systematic Review Unveils the Best Way To Lose Weight
American Society for Metabolic and Bariatric Surgery | June 21, 2024

Systematic reviews of medical literature from 2020 to 2024 indicate that bariatric surgery, also referred to as metabolic or weight-loss surgery, results in the most significant and enduring weight loss compared to treatments with GLP-1 receptor agonists and lifestyle changes. These findings were presented at the 2024 Annual Scientific Meeting of the American Society for Metabolic and Bariatric Surgery (ASMBS).

Researchers found lifestyle interventions such as diet and exercise resulted in an average weight loss of 7.4% but that weight was generally regained within 4.1 years...

Five months of weekly injections of GLP-1 semaglutide resulted in 10.6% weight loss and nine months of tirzepatide produced 21.1% weight loss. However, once treatment stopped, about half the lost weight returned within a year despite which drug was used. If injections were continued, tirzepatide patients plateaued at 22.5% weight loss at 17-18 months. Patients on semaglutide plateaued at 14.9% during the same time period.

Metabolic and bariatric surgery procedures gastric bypass and sleeve gastrectomy demonstrated total weight loss of 31.9% and 29.5% one year after surgery, respectively. Weight loss of approximately 25% was maintained for up to 10 years after surgery.

...“While the new drug treatments show great promise and will lead to more people being successfully treated, particularly if prices come down and insurance coverage improves, we are barely using the best tool we have to fight obesity — metabolic and bariatric surgery, which is safer and more effective than ever before,” said Ann Rogers, MD, ASMBS President-elect and Professor of Surgery at Penn State College of Medicine, who was not involved in the study. “For many people, the risk of death from obesity, diabetes, and heart disease exceeds the risks of surgery.”

Reference: “Effectiveness and Durability of Common Weight Loss Methods” by Megan E Jenkins, Juliane Hafermann, Christine Fielding, Gerhard Prager and Marina Kurian, 11 June 2024, American Society for Metabolic and Bariatric Surgery (ASMBS) 2024 Annual Scientific Meeting. https://asmbsmeeting.com/abstract/effectiveness-and-durability-of-common-weight-...

https://scitechdaily.com/new-systematic-review-unveils-the-best-way-to-lose-weig...

How blockbuster obesity drugs create a full feeling — even before one bite of food
Mariana Lenharo | 27 June 2024

... scientists describe two distinct groups of neurons associated with feeling full: one for pre-meal fullness and one for post-meal fullness. The study also shows that the blockbuster obesity drugs act on those ‘fullness’ neurons, but more research is needed to determine the drug’s exact mechanism ...

The identification of these two populations of neurons is the paper’s key contribution, says Allison Shapiro, a specialist in neurodevelopment at the University of Colorado Anschutz Medical Campus in Aurora who was not involved in the research. It fits in with the anecdotal idea that there are two types of fullness: one that is anticipatory and another that arises in response to eating. “Based on what they've found, it appears that this specific region of the hypothalamus is responsible for both, which is pretty cool.”

The latest blockbuster medications for obesity mimic a hormone called glucagon-like peptide 1 (GLP-1), which controls blood-sugar levels and also acts on the brain to curb appetite. The GLP-1 drugs include semaglutide, sold as Ozempic and Wegovy, and liraglutide, sold as Saxenda and Victoza ...

doi: https://doi.org/10.1038/d41586-024-02106-0

---------------------------------------

Kyu Sik Kim et al. 2024. GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans. Science, 27 Jun 2024,
First Release. DOI: 10.1126/science.adj253 https://www.science.org/doi/10.1126/science.adj2537

Eric Topol (Scripps) @EricTopol | 11:23 PM · Jul 7, 2024:

Challenging dogma: The evidence that obesity is not an energy balance problem but rather a primary metabolic disorder—fuel-partitioning.
----------------------------------------

Mark I. Friedman et al. 2024. Trapped fat: Obesity pathogenesis as an intrinsic disorder in metabolic fuel partitioning (REVIEW). Obesity Reviews. First published: 03 July 2024. https://doi.org/10.1111/obr.13795 https://onlinelibrary.wiley.com/doi/10.1111/obr.13795 Open Access

Summary
Our understanding of the pathophysiology of obesity remains at best incomplete despite a century of research. During this time, two alternative perspectives have helped shape thinking about the etiology of the disorder. The currently prevailing view holds that excessive fat accumulation results because energy intake exceeds energy expenditure, with excessive food consumption being the primary cause of the imbalance. The other perspective attributes the initiating cause of obesity to intrinsic metabolic defects that shift fuel partitioning from pathways for mobilization and oxidation to those for synthesis and storage. The resulting reduction in fuel oxidation and trapping of energy in adipose tissue drives a compensatory increase in energy intake and, under some conditions, a decrease in expenditure. This theory of obesity pathogenesis has historically garnered relatively less attention despite its pedigree. Here, we present an updated comprehensive formulation of the fuel partitioning theory, focused on evidence gathered over the last 80 years from major animal models of obesity showing a redirection of fuel fluxes from oxidation to storage and accumulation of excess body fat with energy intake equal to or even less than that of lean animals. The aim is to inform current discussions about the etiology of obesity and by so doing, help lay new foundations for the design of more efficacious approaches to obesity research, treatment and prevention.

House hearing scheduled for September?

Novo Nordisk, Lilly must cut US prices of weight-loss drugs, Biden says
Patrick Wingrove and Manas Mishra | July 2, 2024
https://www.reuters.com/business/healthcare-pharmaceuticals/biden-says-novo-nord...

How Vitamin D Affects Body Fat Percentage
T Nation | 11 July 2024

...Back in 2020, scientists lined up 47 college athletes to test the fat-loss effects of training and concurrent daily usage of 1,000 IU of vitamin D. They did the blood work and the scans for the three-month study, and then, one month into the project, COVID hit. Gyms shut down. The previously fit athletes stopped training. However, 27 of them kept taking the vitamin D they'd been supplied.

After three months, the scientists re-examined the athletes just to see what happened. The athletes who didn't take vitamin D during the shutdown increased their fat percentage by 1.9 points. But those who did take vitamin D only increased their fat percentage by 0.2 points.

...Vitamin D doesn't work – at least as far as the immune system is concerned – if there aren't sufficient levels of magnesium in the body to help it. It's hard to substantially raise vitamin D levels in the body unless magnesium is there to coax it along.

Most Americans – 80% by some estimates – are deficient in magnesium, and it's even worse in athletes because the mineral sneaks out of the body through sweat...

References
Kawashima I et al. "The impact of vitamin D supplementation on body fat mass in elite male collegiate athletes." Nutr Metab. 20211;18:51.
Arunabh S et al. "Body fat content and 25-hydroxyvitamin D levels in healthy women." J Clin Endocrinol Metab. 2003 Jan;88(1):157-61. PubMed: 12519845.
Salehpour A et al. "A 12-week double blind randomized clinical trial of vitamin d3 supplementation on body fat mass in healthy overweight and obese women." Nutr J. 2012 Sep 22;11:78. PubMed: 22998754.
Dai Q et al. "Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial." Am J Clin Nutr. 2018 Dec 1;108(6):1249-1258. PubMed: 30541089.
RosanoffA et al. "Essential Nutrient Interactions: Does Low or Suboptimal Magnesium Status Interact with Vitamin D and/or Calcium Status?" Adv Nutr. 2016 Jan 15;7(1):25-43. PubMed: 26773013.

https://t-nation.com/t/how-vitamin-d-affects-body-fat-percentage/286607

>1 margd: contd. Butyrate ... beta-glucan in oats and barley

This one fiber may actually be better than any weight loss drug
StudyFinds Staff | Jul 20, 2024

...beta-glucan, a type of fiber found naturally in oats and barley ... consuming foods rich in beta-glucan could help reduce body weight and improve glucose control without the need for expensive medications...

...Mice fed a high-fat diet supplemented with beta-glucan showed significant reductions in weight gain and body fat compared to those on the same diet without the supplement. But the benefits didn’t stop there – the beta-glucan group also demonstrated improved glucose tolerance and insulin sensitivity, both critical factors in metabolic health.

So, what makes beta-glucan so special? The researchers found that it increased energy expenditure in the mice – essentially helping them burn more calories. It’s as if the beta-glucan gave their metabolisms a gentle boost. The mice supplemented with beta-glucan were also more physically active, moving around their cages more than their counterparts.

But the story gets even more interesting when we look at what was happening inside the mice’s bodies, particularly in their gut microbiomes. Beta-glucan supplementation led to unique changes in the types of bacteria present in the gut, most notably increasing the levels of butyrate, a beneficial compound produced when gut bacteria ferment certain fibers.

... ‘Effects mirror benefits seen with Ozempic’ ...

...As for how much beta-glucan can be found in a typical bowl of oatmeal or barley, that will vary on the product. According to a 2021 study, an “efficacious daily dose of 3g beta-glucan is provided in 75g of whole-grain oats (minimum 5.5% beta-glucan) or 55g of oat bran (4% beta-glucan). For an average adult, this quantity is likely to be difficult to achieve on a regular basis.”

Supplementation in the future could be a preferred method by health professionals, though consuming whole-grain oats regularly is still a health-boosting practice for most people...

https://studyfinds.org/beta-glucan-fiber-better-than-weight-loss-drug/
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Elizabeth J Howard et al. 2024. Impact of Plant-Based Dietary Fibers on Metabolic Homeostasis in High-Fat Diet Mice via Alterations in the Gut Microbiota and Metabolites. The Journal of Nutrition, Volume 154, Issue 7, July 2024, Pages 2014-2028. https://doi.org/10.1016/j.tjnut.2024.05.003 https://www.sciencedirect.com/science/article/pii/S0022316624002803

Abstract ... Methods
HFD {high fat diet}-fed mice were supplemented with 5 different fiber types (pectin, β-glucan, wheat dextrin, resistant starch, or cellulose as a control) at 10% (wt/wt) for 18 wk (n = 12/group), measuring body weight, adiposity, indirect calorimetry, glucose tolerance, and the gut microbiota and metabolites...

...Discussion
...Overall, this study investigates the role of various plant-derived dietary fibers, pectin, β-glucan, wheat dextrin, and RS, on metabolic homeostasis. Importantly, β-glucan supplementation in HFD-feeding significantly improved bodyweight, adiposity, energy, and glucose homeostasis, along with increased concentrations of butyrate and changes in bile acid metabolism compared to control-HFD. These data demonstrate the therapeutic potential of β-glucan to attenuate body weight gain and adiposity and improve glucose homeostasis and insulin sensitivity in HFD-fed mice. These findings enhance the current understanding of the potential mechanisms through which β-glucan may be employing its beneficial effects, particularly by identifying gut microbiota-mediated mechanisms upon dietary fiber supplementation.

Scientists Warn: These Common Chemicals May Forever Alter Gut Health, Leading to Lifelong Disease
Penn State | August 19, 2024

...New research led by Penn State reveals that early exposure to ‘forever chemicals’ in the environment permanently disrupts the gut microbiome in mice, potentially leading to the development of metabolic diseases later in life. The findings, published in the journal Environmental Health Perspectives, suggest that similar exposure in early childhood could be a factor in the rising incidence of metabolic disorders, such as obesity and type 2 diabetes, among adults.

The researchers focused specifically on 2,3,7,8-tetrachlorodibenzofuran (TCDF), a widespread persistent organic pollutant (POP) that is a byproduct of waste incineration, metal production, and fossil-fuel and wood combustion. TCDF accumulates in the food chain, and humans are primarily exposed through the consumption of high-fat foods, such as meat, dairy products, and some fish. Babies can be exposed through the consumption of breast milk....

https://scitechdaily.com/scientists-warn-these-common-chemicals-may-forever-alte...
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Yuan Tian et al. 2024. Effects of Early Life Exposures to the Aryl Hydrocarbon Receptor Ligand TCDF on Gut Microbiota and Host Metabolic Homeostasis in C57BL/6J Mice. Environmental Health Perspectives, 14 August 2024. DOI: 10.1289/EHP13356 https://ehp.niehs.nih.gov/doi/10.1289/EHP13356

ABSTRACT
...Results:
TCDF-exposed mice exhibited lower abundances of A. muciniphila, lower levels of cecal short-chain fatty acids (SCFAs) and indole-3-lactic acid (ILA), as well as lower levels of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), findings suggestive of disruption in the gut microbiome community structure and function. Importantly, microbial and metabolic phenotypes associated with early life POP {persistent organic pollutants} exposure were transferable to GF {germ-free} recipients in the absence of POP carry-over. In addition, AHR {aryl hydrocarbon receptor} -independent interactions between POPs and the microbiota were observed, and they were significantly associated with growth, physiology, gene expression, and metabolic activity outcomes of A. muciniphila, supporting suppressed activity along the ILA pathway.

Conclusions:
These data obtained in a mouse model point to the complex effects of POPs on the host and microbiota, providing strong evidence that early life, short-term, and self-limiting POP exposure can adversely impact the microbiome, with effects persisting into later life with associated health implications.

Wow! (Cross-posted from Big Pharma thread.)

Eric Topol (Scripps) @EricTopol | 11:49 AM · Aug 21, 2024 {X}:

Speaking of drug costs, US more than 5-10X other countries for GLP-1
https://healthsystemtracker.org/brief/prices-of-drugs-for-weight-loss-in-the-us-....

Do something.

Table, cost weight-loss drugs in US and peer nations (https://x.com/EricTopol/status/1826285460228100206/photo/1)

Eric Topol {MD, Scripps} @EricTopol | 12:39 PM · Aug 25, 2024 {X}:

A 5-year observational study of ~12,000 individuals with obesity taking GLP-1 drugs (without diabetes) with propensity matched controls
A significant reduction of all-cause mortality (HR 0.23, 95% CI 0.15, 0.34)

Graph probability survival 1800 days (https://x.com/EricTopol/status/1827747599560135093/photo/1)

Other outcomes assessed. Significant reductions of ischemic heart disease (IHD), stroke, heart failure, arrhythmias, atrial fibrillation, acute and chronic kidney disease, allergic reactions

Table GLP-1 RA v comparator per conditions (https://x.com/EricTopol/status/1827747601053335694/photo/1)
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Yu-Nan Huang et al.2024. Long-term safety and efficacy of glucagon-like peptide-1 receptor agonists in individuals with obesity and without type 2 diabetes: A global retrospective cohort study. Diabetes, Obesity, and Metabolism. First published: 22 August 2024. https://doi.org/10.1111/dom.15869 https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15869 Open read: https://www.openread.academy/en/paper/reading?corpusId=507042902

Abstract
Aim
We aimed to investigate the long-term impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on thyroid function, cardiovascular health, renal outcomes and adverse events in individuals with obesity and without type 2 diabetes (T2D).

Materials and Methods
In this observational cohort study, we used propensity score matching to construct comparable cohorts of individuals with obesity and without T2D who were new to GLP-1 RA treatment and those who did not receive glucose-lowering medications. In total, 3,729,925 individuals with obesity were selected from the TriNetX Global Network, with an index event* between 1 January 2016 and 31 March 2024. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event.

Results
After propensity score matching, the study included 12,123 individuals in each group. GLP-1 RA treatment was associated with a significantly lower risk of all-cause mortality (hazard ratio 0.23...) and several cardiovascular complications, including ischaemic heart disease, heart failure, arrhythmias, hypertension, stroke and atrial fibrillation ... GLP-1 RAs were also associated with a lower risk of acute kidney injury and allergic reactions. These protective effects were consistent across various subgroups and regions.

Conclusions
In this large observational study, GLP-1 RAs showed long-term protective effects on cardiovascular health, renal outcomes and adverse events in individuals with obesity and without T2D. Our findings suggest that GLP-1 RAs may offer a comprehensive approach to managing obesity and its related comorbidities, potentially improving overall health and survival in this population.

* Issa J. Dahabreh and David M. Kent 2011. Index event bias: an explanation for the paradoxes of recurrence risk research. JAMA. 2011;305(8):822-823. doi:10.1001/jama.2011.163 https://jamanetwork.com/journals/jama/article-abstract/645707

Carbs or fats for breakfast? Which is best for healthy weight in men vs women?

A carbohydrate-rich breakfast for men and a fat-rich breakfast for women gets the day off to a good start, a new study suggests.

While women store more fat than men, they also burn it faster to obtain energy, according to computer modeling used in the study.

https://www.medicalnewstoday.com/articles/carbs-or-fats-for-breakfast-which-is-b...
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Stéphanie M.C. Abo and Anita T. Layton 2024. Modeling sex-specific whole-body metabolic responses to feeding and fasting. Computers in Biology and Medicine, Volume 181, October 2024, 109024. https://doi.org/10.1016/j.compbiomed.2024.109024 https://www.medicalnewstoday.com/articles/carbs-or-fats-for-breakfast-which-is-b...

...4. Conclusion
We developed a comprehensive, multi-scale, sex-specific model of energy metabolism following various mixed meals. Our model aligns well with experimental data. Our predictions indicate that sex-related metabolic differences are more pronounced during short-term fasting. In summary, women tend to preserve more fat than men during the absorptive period but exhibit significantly higher fat oxidation during the postabsorptive period. We hypothesize that this increased reliance on fat metabolism in females is influenced by sex differences in liver and adipose tissue, for which we propose a candidate underlying mechanism. Specifically, the female liver diverts more glycerol towards gluconeogenesis, consequently increasing its rate. However, the female liver conserves glycogen more than the male liver, resulting in reduced glycogenolysis and lower glucose output compared to the male model. This reduction in arterial glucose promotes FFA {free fatty acid*} oxidation by other organs and tissues, excluding the brain. Computational biology offers promising avenues for refining whole-body metabolic models. Integrating sex-specific data and parameters into multi-scale frameworks holds the potential to enhance our understanding of human metabolism and its modulation by sex. By considering the intricate interplay among organs, hormones, and metabolic pathways, these models can offer valuable insights into the underlying mechanisms driving sex-specific metabolic responses.

* https://www.sciencedirect.com/topics/neuroscience/free-fatty-acids

Scientists Discover Amazing New Benefit of Ozempic: Reducing Alcohol and Opioid Addiction
Society for the Study of Addiction | October 18, 2024

... The study found that people with OUD (opioid use disorder) who had a GLP-1 RA or GIP prescription had a 40% lower rate of opioid overdose compared with those who did not have a prescription.

... people with AUD (alcohol use disorder) who had a GLP-1 RA or GIP prescription had a 50% lower rate of alcohol intoxication compared with those who did not have a prescription...

https://scitechdaily.com/scientists-discover-amazing-new-benefit-of-ozempic-redu...
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Fares Qeadan et al. 2024. The association between glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonist prescriptions and substance-related outcomes in patients with opioid and alcohol use disorders: A real-world data analysis. Addiction, 16 October 2024. DOI: 10.1111/add.16679

>1 margd: contd.

One Type of Fiber May Have Weight Loss Benefits Similar to Ozempic
Carly Cassella | 25 October 2024

...Only beta-glucan (oats, barley) was found to increase the number of Ileibacterium found in the mouse intestine. Other studies on mice have linked this bacterium to weight loss.

Sure enough, long before the 10-week marker, mice fed beta-glucan showed reduced body weight and body fat content compared to mice fed other forms of fiber.

The findings align with another recent study by Duca, which fed barley flour, rich in beta-glucan, to rodents. Even though the rats continued eating just as much of their high-fat diet as before, their energy expenditure increased and they lost weight anyway.

A similar outcome was observed in mice fed beta-glucan in the new study. These animals also showed increased concentrations of butyrate in their guts, which is a metabolite made when microbes break down fiber.

Butyrate induces the release of glucagon-like peptide-1 (GLP-1), which is the natural protein that synthetic drugs like Ozempic mimic to stimulate insulin release...

https://www.sciencealert.com/one-type-of-fiber-may-have-weight-loss-benefits-sim...
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Elizabeth J Howard et al. 2024. Impact of Plant-Based Dietary Fibers on Metabolic Homeostasis in High-Fat Diet Mice via Alterations in the Gut Microbiota and Metabolites. The Journal of Nutrition, Volume 154, Issue 7, July 2024, Pages 2014-2028. https://doi.org/10.1016/j.tjnut.2024.05.003 https://www.sciencedirect.com/science/article/pii/S0022316624002803?via%3Dihub

Inulin available as a powder supplement generates butyrate. Not sure from quick scan whether / how to nudge this pathway, though...

Maria Dolores Moya-Garzon et al. 2024. A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites. Cell, 12 November 2024. DOI: 10.1016/j.cell.2024.10.032 https://www.cell.com/cell/fulltext/S0092-8674(24)01214-5

Laura C. Hinte et al. 2024. Adipose tissue retains an epigenetic memory of obesity after weight loss. Nature 18 Nov 2024. https://www.nature.com/articles/s41586-024-08165-7 . Open access.

Abstract
Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity ... However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes ... Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic ‘yo-yo’ effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.

https://x.com/EricTopol/status/1858544043271049382/photo/1

Biden proposes Medicare and Medicaid cover costly weight-loss drugs for millions of obese Americans
AMANDA SEITZ | November 26, 2024

... The costly proposal from the U.S. Department of Health and Human Services immediately sets the stage for a showdown between the powerful pharmaceutical industry and Robert F. Kennedy Jr., an outspoken opponent of the weight-loss drugs who, as President-elect Donald Trump’s nominee to lead the agency, could block the measure.

The rule would not be finalized until January, days after Trump takes office. A bipartisan coalition of congressional members has lobbied for the drugs to be covered by Medicare, saying it could save the government from spending billions of dollars on treating chronic ailments that stem from obesity. While it’s unclear where Trump himself stands on coverage of the weight-loss drugs, his allies and Cabinet picks who have vowed to cut government spending could balk at the upfront price tag...

https://apnews.com/article/ozempic-biden-rfk-jr-trump-antiobesity-drugs-caaa2f88...
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Obesity Drugs Would Be Covered by Medicare and Medicaid Under Biden Proposal
The proposed rule could give millions of Americans access to the new drugs; it would also put pressure on the federal budget.
Margot Sanger-Katz | Nov. 26, 2024

... legislation passed 20 years ago prevents Medicare from covering drugs for “weight loss.”

The new proposal sidesteps that restriction, specifying that the drugs would be covered to treat the disease of obesity and prevent its related conditions.

... Robert F. Kennedy Jr., his choice to lead the Department of Health and Human Services, has suggested that obesity should be tackled through healthy eating, not drugs.

“If we just gave good food, three meals a day, to every man, woman and child in our country, we could solve the obesity and diabetes epidemic overnight,” Mr. Kennedy said on Fox News before the election.

Dr. Mehmet Oz, Mr. Trump’s choice to lead C.M.S., has been more enthusiastic; he featured patients who took the drugs on his old television talk show. Dr. Oz’s portfolio would include Medicare and Medicaid policy, but he would report to Mr. Kennedy. ...

Given Mr. Kennedy’s skepticism, and the new drugs’ potentially large cost, Trump officials might not have proposed a coverage requirement. But they may now face pressure to approve it.

https://www.nytimes.com/2024/11/26/upshot/obesity-drugs-medicare-medicaid.html?u...

Prevents declines in endothelial function after a high-fat meal during mental stress /challenge,
e.g. increasingly difficult math:
2 cups of green tea, 5.5 tbsp of unprocessed {NON-ALKALIZED} cocoa or 300 g of berries.
______________________________________________

Cocoa could protect you from the negative effects of fatty foods during mental stress - study
New research has found that a flavanol-rich cocoa drink can protect the body’s vasculature against stress even after eating high-fat food.
U of Birmingham | 18 November 2024

https://www.birmingham.ac.uk/news/2024/cocoa-could-protect-you-from-the-negative....
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Rosalind Baynham et al. 2024. Cocoa flavanols rescue stress-induced declines in endothelial function after a high-fat meal, but do not affect cerebral oxygenation during stress in young, healthy adults Check for updates. Food and Function, Issue 2023, 2024. https://pubs.rsc.org/en/content/articlelanding/2024/fo/d4fo03834g

Abstract
Food choices during stressful periods often worsen, which can influence the impact of stress on vascular health. For instance, fat consumption impairs the recovery of endothelial function following mental stress, while flavanols have been shown to enhance recovery. This randomised, counterbalanced, double-blinded, crossover, postprandial intervention study examined whether flavanols consumed in combination with fat can mitigate the negative impact of fat on stress-induced impairments in endothelial function. Twenty-three young, healthy males and females ingested a high-fat meal (56.5 g fat) with high-flavanol (150 mg (−)-epicatechin) or low-flavanol (less than 6 mg (−)-epicatechin) cocoa 1.5 hours before an 8-minute mental stress task. The primary outcome, brachial flow-mediated dilatation (FMD), was assessed at pre-intervention baseline and 30 and 90 minutes post-stress. Pre-frontal cortical oxygenation was assessed post-meal at rest and during stress. Forearm blood flow (FBF), blood pressure (BP), cardiovascular activity, common carotid artery (CCA) diameter and blood flow and mood were assessed before, during and/or after stress. FMD was impaired at 30 and 90 minutes post-stress after the low-flavanol cocoa. High-flavanol cocoa attenuated FMD impairments at 30 minutes and improved FMD at 90 minutes post-stress. Mental stress induced similar increases in cortical oxygenation, FBF, BP, cardiovascular activity, and disruptions to mood, in both conditions. CCA diameter increased and CCA retrograde blood flow decreased post-stress, with no difference between conditions. In summary, flavanols can counteract declines in endothelial function induced by consuming fat in the context of stress, but do not impact cerebral oxygenation. These findings can have important implications for flavanol-rich dietary choices to protect the vasculature from stress.

Conclusions
In summary, this study demonstrates that flavonoid-rich foods have the potential to acutely protect endothelial function against poor food choices, such as high-fat snacks, during episodes of stress in young healthy adults. It further suggests that such protection does not extend to the cerebral vasculature. However, our data indicate that the size of the flavanol effect in the brain is smaller, and a larger sample is needed to clarify the protective effects in the brain during stress. Given the prognostic value of FMD for future risk of CVD,7 these findings are clinically relevant, particularly given the documented prevalence of stress and the trend towards increased consumption of high-fat foods during periods of heightened stress. This work has relevance for application in everyday diet, as the administered dose of flavanols could be achieved through consumption of, for instance, 2 cups of green tea, 5.5 tbsp of unprocessed cocoa or 300 g of berries.106 As such, our data have important implications for future acute dietary recommendations to protect the vasculature during stressful periods.

*"Impaired endothelial function is recognized as an early and modulating process in the pathophysiology of atherosclerotic cardiovascular disease1. Endothelial function is often quantified by flow-mediated dilation (FMD), which represents the endothelium-dependent relaxation of a conduit artery-typically the brachial artery – due to an increased blood flow. Brachial artery reactivity is a frequently used non-invasive ultrasonographic assessment of FMD that indicates endothelium-dependent response to shear stress2. This measure is a marker for increased cardiovascular risk3, and correlates with impaired endothelium-dependent relaxation in the coronary arteries" https://pmc.ncbi.nlm.nih.gov/articles/PMC1847451/

Eric Topol ‪@erictopol.bsky.social‬ | March 25, 2025 at 10:21 AM
Physician-scientist

Does intermittent fasting improve health outcomes?
It's not clearcut.
A very good review of what is known


{Paywall?}

Nic Fleming | 25 March 2025. Fasting for weight loss is all the rage: what are the health benefits? (NEWS FEATURE). Nature 639, 855-857 (2025). doi: https://doi.org/10.1038/d41586-025-00895-6 https://www.nature.com/articles/d41586-025-00895-6

Intermittent fasting has gained a following, in part because of tantalizing hints that it can boost cognition, fend off cancer and even slow ageing.

... Although most researchers who study intermittent fasting agree that it can help people to lose weight, they’re split on whether there are any benefits beyond those that come from simply eating less...

Study strengthens link between maternal diabetes and autism
Nancy Lapid | April 8, 2025

...The risks for children of mothers with diabetes during pregnancy were 25% higher for autism, 30% higher for attention deficit hyperactivity disorder and 32% higher for intellectual disability. They were also 20% higher for trouble with communication, 17% higher for movement problems and 16% higher for learning disorders than in children whose mothers did not have diabetes while pregnant.

Diabetes diagnosed before pregnancy appeared to confer a 39% higher risk for one or more of these neurodevelopmental disorders compared with gestational diabetes that begins in pregnancy and often resolves afterward...

https://www.reuters.com/business/healthcare-pharmaceuticals/study-strengthens-li...
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Wenrui Ye et al. 2025. Association between maternal diabetes and neurodevelopmental outcomes in children: a systematic review and meta-analysis of 202 observational studies comprising 56·1 million pregnancies. The Lancet Diabetes and Endocrinology, 7 April 2025. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(25)00036-1/abstr...

Abstract
... Findings
202 studies, involving 56 082 462 mother–child pairs, were included in the meta-analysis. Of these, 110 (54%) examined gestational diabetes, while 80 (40%) investigated pre-gestational diabetes. Among the total studies reviewed, 169 (84%) exclusively focused on children and adolescents aged up to 18 years. In studies adjusting for at least one key confounder, maternal diabetes was associated with increased risks of all types of neurodevelopmental disorders as well as lower intelligence and psychomotor scores. In studies adjusting for multiple confounders ..., children exposed to maternal diabetes had an increased risk of any neurodevelopmental disorder (risk ratio 1·28 ...), autism spectrum disorder (1·25 ...), attention-deficit hyperactivity disorder (1·30 ...), intellectual disability (1·32 ...), specific developmental disorders (1.27...), communication disorder (1·20 ...), motor disorder (1·17 ...), and learning disorder (1·16 ...), compared with unexposed children. Maternal pre-gestational diabetes was more strongly associated with the risk of most neurodevelopmental disorders in children than gestational diabetes (risk ratio 1·39 ... vs 1·18 ...).

Interpretation
Maternal diabetes is associated with an increased risk of neurodevelopmental disorders and impaired neurodevelopmental performance in children. Further high-quality research is needed to establish causality and clarify the associations between specific types of diabetes and the full spectrum of neurodevelopmental disorders.

Your Body Fat May Be Shaped by The Month You Were Conceived
Carly Cassella | 08 April 2025

... Among 356 healthy young male volunteers, researchers in Japan found that those who were conceived in a cold season showed relatively higher brown adipose tissue activity. Brown adipose tissue is a type of fat that burns energy, keeps us warm, and helps regulate blood sugar.

Along with increased brown fat activity, participants also showed increased energy expenditure, a lower body mass index (BMI), and less fat accumulation around their organs, which indicates better metabolic health overall.

In those who are deemed overweight or obese, brown fat activity is often lacking...

https://www.sciencealert.com/your-body-fat-may-be-shaped-by-the-month-you-were-c...
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Open access:
Takeshi Yoneshiro et al. 2025. Pre-fertilization-origin preservation of brown fat-mediated energy expenditure in humans. Nature Metabolism (7 April 2025). https://www.nature.com/articles/s42255-025-01249-2

Abstract
Environmental thermal stress substantially affects cellular plasticity of thermogenic adipocytes and energy balance through transcriptional and epigenetic mechanisms in rodents. However, roles of cold-adaptive epigenetic regulation of brown adipose tissue (BAT) in systemic energy metabolism in humans remained poorly understood. Here we report that individuals whose mothers conceived during cold seasons exhibit higher BAT activity, adaptive thermogenesis, increased daily total energy expenditure and lower body mass index and visceral fat accumulation. Structural equation modelling indicated that conception during the cold season protects against age-associated increase in body mass index through BAT activation in offspring. Meteorological analysis revealed that lower outdoor temperatures and greater fluctuations in daily temperatures during the fertilization period are key determinants of BAT activity. These findings suggest that BAT metabolic fate and susceptibility of metabolic diseases are preprogrammed by the epigenetic inheritance of cold exposure before the fertilization in humans.

At nutritionfacts.org, plant-diet advocate Dr Greger has posted several observational studies comparing health of American v African blacks. (Americans on western diet "enjoyed" all of the usual western diseases, while Africans on traditional diets did not.) Below is rigorous test of the effects of western v. traditional diet, this one from the Kilimanjaro region in Northern Tanzania:

Diet high in fiber, fermented foods could keep inflammatory diseases at bay
Kelsey Costa | April 7, 2025

Chronic inflammation is a major driver of lifestyle-related diseases, like heart disease and type 2 diabetes.
New research highlights how profoundly a modern Western diet, high in processed foods and low in whole plant-based foods, can contribute to this chronic inflammation.
Experts recommend adopting more traditional, plant-rich diets to reduce inflammation and promote optimal immune function and metabolic health.

... just 2 weeks of adopting a Western diet over a traditional African diet can lead to increased inflammation, weakened immune responses, and disrupted metabolic pathways tied to lifestyle-related diseases.

In contrast, switching from a Western diet to a traditional African diet or consuming traditional fermented beverages Mbege, a traditional fermented drink made with bananas and millet may have anti-inflammatory benefits.

While more research is needed, these results support the idea that largely plant-based heritage diets — like traditional African, Mediterranean, and Latin American diets — can improve health and lower the risk of lifestyle-related diseases.

The traditional African diet in this study was rich in:

black tea
green vegetables
legumes
plantains
root and tuber crops (like sweet potato, cassava, and taro)
ancient grains (like millet and sorghum).

These foods are high in dietary fiber and bioactive compounds, such as polyphenols, which help reduce inflammation and promote metabolic health. They also encourage a healthy gut microbiome and the production of beneficial metabolites that enhance overall health and well-being.

... In addition, {Thomas M. Holland, MD, MS, a physician-scientist and assistant professor at the RUSH Institute for Healthy Aging, RUSH University, College of Health Sciences, who was not involved in the study} emphasized the potential advantages of traditional African fermented foods and beverages, like Mbege, which “play a critical role by enriching the gut microbiome with beneficial microbes and bioactive metabolites that enhance immune function.”

He noted that specific compounds present in Mbege, such as flavonoids, also likely contributed to improved immune responses and vascular health in the individuals who consumed the fermented beverage...

https://www.medicalnewstoday.com/articles/diet-high-in-fiber-fermented-foods-cou...
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Open access
Godfrey S Temba et al. 2025. Immune and metabolic effects of African heritage diets versus Western diets in men: a randomized controlled trial. Nature Medicine, 3 April 2025. https://www.nature.com/articles/s41591-025-03602-0

Abstract

African heritage diets are increasingly being replaced by Western-style dietary patterns because of urbanization, economic development, increased access to processed foods, globalization and changing social norms. The health consequences of this nutrition transition are not well understood. We conducted a randomized controlled trial in the Kilimanjaro region in Northern Tanzania to investigate the immune and metabolic effects of switching between Kilimanjaro heritage-style and Western-style diets for 2 weeks and consuming a traditional fermented banana beverage (‘Mbege’) for 1 week. Seventy-seven young and healthy volunteers assigned male at birth, some living in urban areas and some living in rural areas, were recruited in the trial. Primary outcomes were changes in the immune and metabolic profile before and after the intervention and at the 4-week follow-up. The switch from heritage-style to Western-style diet affected different metabolic pathways associated with noncommunicable diseases and promoted a pro-inflammatory state with impaired whole-blood cytokine responses to microbial stimulation. In contrast, the switch from Western-style to heritage-style diet or consuming the fermented beverage had a largely anti-inflammatory effect. Some of the observed changes in the immune and metabolic profiles persisted at the follow-up, suggesting a sustained impact from the short-term intervention. These findings show the metabolic and immune effects of dietary transitions and the consumption of fermented beverages, underscoring the importance of preserving indigenous dietary practices to mitigate noncommunicable disease risk factors in sub-Saharan Africa.

Weight-loss drugs tested in head-to-head trial
James Gallagher | 11 May 2025

32% of people lost a quarter of their body weight on Mounjaro {Tirzepatide} compared to 16% on Wegovy {Semaglutide}
Those on Mounjaro lost an average of 18cm from their waistlines compared with 13cm on Wegovy.
Those on Mounjaro had better blood pressure, blood sugar and cholesterol levels.
Both had similar levels of side-effects.
Women tended to lose more weight than men.

https://www.bbc.com/news/articles/cy75dk8kjr1o
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Louis J. Aronne et al. 2025. Tirzepatide {Mounjaro} as Compared with Semaglutide {Wegovy} for the Treatment of Obesity. NEJM May 11, 2025. https://www.nejm.org/doi/full/10.1056/NEJMoa2416394

Abstract
Background
Tirzepatide and semaglutide are highly effective medications for obesity management. The efficacy and safety of tirzepatide as compared with semaglutide in adults with obesity but without type 2 diabetes is unknown.
Methods
In this phase 3b, open-label, controlled trial, adult participants with obesity but without type 2 diabetes were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. The primary end point was the percent change in weight from baseline to week 72. Key secondary end points included weight reductions of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72.
Results
A total of 751 participants underwent randomization. The least-squares mean percent change in weight at week 72 was −20.2% ... with tirzepatide and −13.7% ... with semaglutide ... The least-squares mean change in waist circumference was −18.4 cm ... with tirzepatide and −13.0 cm ... with semaglutide ... Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%. The most common adverse events in both treatment groups were gastrointestinal, and most were mild to moderate in severity and occurred primarily during dose escalation.
Conclusions
Among participants with obesity but without diabetes, treatment with tirzepatide was superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72...

AMA Clinical Guidelines Synopsis:

Eva S. Liu et al 2025. Vitamin D for Prevention of Disease. JAMA, April 23, 2025
2025;333;(20):1824-1825. doi:10.1001/jama.2025.2278 https://jamanetwork.com/journals/jama/fullarticle/2833140

Selected recommendations

In addition to the recommended dietary reference intake (DRI), additional empirical vitamin D from fortified foods, multivitamins, or oral supplements should be started without testing for 25-hydroxyvitamin D (25OHD) levels (conditional recommendation CR; low certainty of evidence COE) for

... Adults with prediabetes, to potentially decrease risk of progression to diabetes. The average daily dose of supplemental vitamin D used in clinical trials was 3500 IU, although participants could continue vitamin D supplements up to 1000 IU (CR; moderate COE).

Routine screening of serum 25(OH)D levels in healthy children and adults is not recommended (CR; very low COE). Healthy people should consume the DRI (600 IU for ages 1-70 years; 800 IU for ages 70-74 years).

How maternal obesity also affects the next generation
Science News Highlights

Children born to obese mothers are at higher risk of developing metabolic disorders, even if they follow a healthy diet themselves. A new study offers an explanation for this phenomenon. In obese mice, certain cells in the embryo’s liver are reprogrammed during pregnancy. This leads to long-term changes in the offspring’s metabolism. The researchers believe that these findings could also be relevant for humans. The study has now been published in the journal Nature...

https://sciencemission.com/Kupffer-cell-programming--triggers-fatty-liver-diseas...
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Hao Huang et al. 2025. Kupffer cell programming by maternal obesity triggers fatty liver disease. Nature 18 June 2025. https://doi.org/10.1038/s41586-025-09190-w https://www.nature.com/articles/s41586-025-09190-w Open access

Abstract
Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis... Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions... Throughout development and adulthood, KCs perform distinct core functions that are essential for liver and organismal homeostasis, including supporting fetal erythropoiesis, postnatal erythrocyte recycling and liver metabolism...

However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood...

... results establish developmental perturbation of KC functions as a causal factor in fatty liver disease in adulthood and position fetal-derived macrophages as critical intergenerational messengers within the concept of developmental origins of health and diseases.

Weight loss alters adipose tissue beyond just reducing fat

The study, published in the journal Nature, compared samples of fat tissue from healthy weight individuals with samples from people with severe obesity (BMI over 35) undergoing bariatric weight loss surgery. The weight loss group had fat samples taken during surgery and more than five months after surgery, at which point they had lost an average of 25 kg.

The researchers analysed gene expression in more than 170,000 cells that made up the fat tissue samples, from 70 people.

They unexpectedly found that weight loss triggers the breakdown and recycling of fats called lipids. This recycling process could be responsible for burning energy and reversing the harmful build-up of lipids in other organs like the liver and pancreas. The researchers say that further study will be needed to establish if lipid recycling is linked to the positive effects of weight loss on health, such as remission of type 2 diabetes.

They also found that the weight loss cleared out senescent cells, which are ageing and damaged cells that accumulate in all tissues. The senescent cells cause harm because they no longer function properly and release signals that lead to tissue inflammation and scarring.

In contrast, the researchers found that weight loss did not improve the effects of obesity on certain aspects of the immune system. They found that inflammatory immune cells, which infiltrated the fat of people with obesity, did not fully recover even after weight loss. This type of inflammatory cell memory could be harmful in the long term if people regain weight.

{Via Facebook} https://sciencemission.com/Weight-loss-alters-adipose-tissue
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Antonio M. A. Miranda et al. 2025. Selective remodelling of the adipose niche in obesity and weight loss. Nature (9 July 2025). https://doi.org/10.1038/s41586-025-09233-2 https://www.nature.com/articles/s41586-025-09233-2. Open access

Abstract
... We discover selective vulnerability to senescence in metabolic, precursor and vascular cells and reveal that senescence is potently reversed by weight loss. We define gene regulatory mechanisms and tissue signals that may drive a degenerative cycle of senescence, tissue injury and metabolic dysfunction. We find that weight loss reduces adipocyte hypertrophy and biomechanical constraint pathways, activating global metabolic flux and bioenergetic substrate cycles that may mediate systemic improvements in metabolic health. In the immune compartment, we demonstrate that weight loss represses obesity-induced macrophage infiltration but does not completely reverse activation, leaving these cells primed to trigger potential weight regain and worsen metabolic dysfunction. Throughout, we map cells to tissue niches to understand the collective determinants of tissue injury and recovery. Overall, our complementary single-nucleus and spatial datasets offer unprecedented insights into the basis of obese AT dysfunction and its reversal by weight loss and are a key resource for mechanistic and therapeutic exploration.

Han Wu et al. 2025. Trajectory of the body weight after drug discontinuation in the treatment of anti-obesity medications (Review). BMC Medicine volume 23, Article number: 398 (22 July 2025). https://doi.org/10.1186/s12916-025-04200-0 https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-025-04200-0 Open access

ABSTRACT...
Results
At week 4 after discontinuation, compared with the control group, AOM {anti-obesity medication} treatment still had weight loss effect (WMD =  − 0.32 kg ...). At 8 weeks after drug discontinuation, AOMs were associated with significant weight regain compared with the control group (WMD = 1.50 kg ...). The weight regain trend remained at 12 and 20 weeks (WMD = 1.76 kg ...; WMD = 2.50 kg ..;). Among the different subgroups of AOMs, significant weight regain after 12 weeks of drug discontinuation was observed only in studies with glucagon-like peptide 1 receptor agonist (GLP-1 RA) related drugs. In addition, studies in which weight loss was greater during treatment than in the control group and studies in which lifestyle interventions were continued observed significant weight gain after drug discontinuation.

Conclusion
Significant weight regain occurred 8 weeks after discontinuation of AOMs and was sustained through 20 weeks. Different weight regain was observed in subjects with different characteristics. Studies with longer follow-up duration are required to further investigate the potential factors associated with weight change after discontinuation of treatment.

,

Chemical {BPA} linked to low sperm count, obesity and cancer found in dummies {aka soohers, pacifiers}, tests find
Damien Gayle | 18 Oct 2025

"... Dummies made by the Dutch multinational Philips, the Swiss oral health specialists Curaprox and the French toy brand Sophie la Girafe were found to contain bisphenol A (BPA), according to laboratory testing by dTest, a Czech consumer organisation. Philips said they had carried out subsequent testing and found no BPA, while Sophie la Girafe said the amount found was insignificant.

All three dummies were marketed as either “BPA- free” or “natural rubber”.

BPA is a synthetic chemical used in the production of plastics, but it has a structure similar to the female hormone, oestrogen, which it mimics in the bodies of humans and other animals...

https://www.theguardian.com/society/2025/oct/18/chemical-linked-impaired-sexual-...

Study finds hidden blood mutations spark obesity, diabetes and liver disease
Leah Buletti | October 13, 2025

"... As part of their study, the researchers put a genetic mutation commonly involved in clonal hematopoiesis into the blood system of otherwise healthy mice. Mice with the mutation started to eat more and gained weight more rapidly than those without the mutation. They developed high blood sugar and were more prone to liver problems.

The effects were even stronger when mice were fed a high-fat, high-sugar “Western” diet — nutritionally similar to a Big Mac, French fries and milkshake diet: Their weight exploded..."

https://news.ufl.edu/2025/10/blood-mutations/
-----------------------------------------------------

Bowen Yan et al. 2025. Clonal hematopoiesis driven by Dnmt3a mutations promotes metabolic disease development in mice. Journal of Clinical Investigation. Published September 30, 2025. https://doi.org/10.1172/JCI197100
https://www.jci.org/articles/view/197100 . Open Access

Soybean oil may contribute to obesity, new study shows
Corrie Pelc | December 5, 2025

"For a healthy weight, you may want to avoid soybean oil, a new study suggests.

Soybean oil encompasses 57% of all cooking oils used in the United States, and 30% globally.
More than 50% of soybean oil is made of an omega-6 fatty acid called linoleic acid.
Past studies show that consuming too much soybean oil or omega-6 fatty acids may increase your risk for certain health concerns, such as obesity.
A new study sheds light on how soybean oil might contribute to a person’s obesity risk.

... To help reduce a person’s soybean oil consumption, {Dietician Monique} Richard recommended:
Read ingredient lists, not front-of-package claims. If soybean oil, vegetable oil, or canola oil appear in the first few ingredients, that food is likely heavily processed. There may be a more wholesome option or healthier alternative.
Choose whole foods over ultra-processed snacks. The largest source of soybean oil in the American diet is not home cooking — it’s commercial packaged foods, fried foods, and restaurant offerings. Use fresh, frozen, or canned produce when possible. Look for whole grain options like oats, bulgar, quinoa, and brown rice versus pre-packaged noodles, crackers, or pasta kits.
Cook more at home, even 1–2 meals per week. That way you have control over the ingredients, sodium, sugar, and oils used. Look for recipes that have simple, whole ingredients that) can be batch cooked for more meals later in the week.
Swap frying for roasting, sautéing, grilling, or air-frying. These methods both reduce oil use and total calorie density.
Choose whole soy foods for natural goodness. Foods such as tofu, tempeh, or soybeans in their pod, aka edamame, are not part of this concern. They are nutrient-dense, fiber-rich, and associated with many health benefits.

Richard offered these tasty soybean oil alternatives, which also have added benefits:
olive oil (extra-virgin, cold-pressed) — great for dressings, marinades, and cooking; benefits have been identified in numerous research studies related to heart and cognitive health
avocado oil — neutral flavor, tolerates higher heat, great everyday option
sesame or peanut oil — a slightly nutty flavor and aroma; excellent in Asian, African, and Middle Eastern-inspired dishes; delivers antioxidants and polyphenols while complimenting flavor profiles of other herbs and spices.
walnut or flaxseed oil — for use at cool or room temperature to top parfaits, desserts, or make dressings..."

https://www.medicalnewstoday.com/articles/soybean-oil-may-contribute-to-obesity-...
--------------------------------------------------------------

Deol, Poonamjot et al. 2025. P2-HNF4α Alters Linoleic Acid Metabolism and Mitigates Soybean Oil-Induced Obesity: Role for Oxylipins. Journal of Lipid Research, Volume 0, Issue 0, 100932. https://www.jlr.org/article/S0022-2275(25)00195-6/fulltext

ABSTRACT
Oxylipins – oxidized metabolites of polyunsaturated fatty acids (PUFAs) – are associated with several pathological conditions. We previously showed that oxylipin metabolites of linoleic acid (LA) and alpha-linolenic acid positively correlate with obesity in wild-type (WT) mice fed a high fat diet (35% kcal fat) based on soybean oil (SO). Here, we compare the effect of the SO diet (10% kcal LA) to an isocaloric diet based on coconut oil (CO) that is low in LA (2% kcal) in HNF4α exon swap male mice that express only the P2 form of HNF4α (α7HMZ). α7HMZ mice gained significantly less weight on the SO diet than WT mice and exhibited neither glucose intolerance nor fatty liver as did the WT mice. Untargeted metabolomics of the liver revealed increased levels of LA and decreased levels of PUFA-derived C18 diols in α7HMZ compared to WT. Proteomics identified decreased levels of several enzymes involved in PUFA metabolism (CYP2Cs, EPHX1, FADS2, ACOX1/2) as the likely cause of decreased diols. Correlation analysis of hepatic oxylipins with body weight, coupled with a 16-week treatment with a soluble epoxide inhibitor (sEHI), identified the oxylipins most likely to be potential drivers of obesity as 9,10-DiHOME, 12,13-DiHOME, 9,10-DiHODE and 12,13-DiHODE. Finally, while neither the CO nor SO diet induced a pro-inflammatory cytokine profile in the liver, docosahexaenoic acid (DHA), several tricarboxylic acid cycle intermediates and glycerol-alpha-phosphate and β-hydroxybutyrate were increased in α7HMZ, suggesting a potential role for mitochondria in the resistance to diet-induced obesity.

Common nutrient {choline} turns our guts into diabetes-fighting chemical factories
Michael Franco | December 09, 2025

"... When a person consistently eats a high fat diet, it can trigger chronic inflammation in the body through a combination of hormonal disruption, immune signaling, and cellular stress. That inflammation, in turn, can lead to insulin resistance, a state where our cells no longer properly respond to insulin, a hormone that allows the glucose in our blood to move into our cells for use as energy. This state can lead to type 2 diabetes where blood sugar levels spike and our pancreas struggles to pump out enough insulin to process it.

The researchers found that one of the chemicals involved in this cascade of negative effects is the immune-system protein IRAK4, which triggers inflammation in the presence of a high-fat diet as a sort of alarm bell. When that protein is expressed for an extended period of time, it leads to insulin resistance and diabetes.

The good news, however, is that the team also discovered a way to turn IRAK4 off.
Using mice, human cell models, and molecular target-screening, the scientists found that when the nutrient choline hits the gut, microbes convert it into a metabolite called trimethylamine (TMA). TMA, in turn, binds to IRAK4, blocks its activity, reduces inflammation, and restores insulin sensitivity. Choline is found in a wide range of foods but is particularly prominent in eggs, organ meats, fish, milk and dairy, as well as in beef, pork, and chicken...

https://newatlas.com/diet-nutrition/gut-microbiome-diabetes/
-----------------------------------------------------------

Chilloux, J., Brial, F., Everard, A. et al. Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01413-8 https://www.nature.com/articles/s42255-025-01413-8 OPEN ACCESS

Abstract
The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome {the entire set of protein kinases in an organism's genome, crucial for cell signaling, especially in humans where there are over 500} in the microbial–mammalian chemical crosstalk.

Five ways weight-loss jabs are changing spending habits
Esyllt Carr | 1/24/2026

Buying groceries: The rise of more nutrient-dense foods
Dining out: 'I used to go to a restaurant once a week. Now I don't'
Drinking: 'A strong trend towards sobriety'
Fashion: A wardrobe that no longer fits
Beauty, health and fitness: More people going to the gym

https://www.bbc.com/news/articles/cj6wy85l3x5o

Chaoqun Huang et al. 2022. Studies on the fat mass and obesity-associated (FTO) gene and its impact on obesity-associated diseases (review). Genes Dis. 2022 May 6;10(6):2351-2365. doi: 10.1016/j.gendis.2022.04.014. https://www.sciencedirect.com/science/article/pii/S235230422200112X

"Abstract
Obesity has become a major health crisis in the past ∼50 years. The fat mass and obesity-associated (FTO) gene, identified by genome-wide association studies (GWAS), was first reported to be positively associated with obesity in humans. Mice with more copies of the FTO gene were observed to be obese, while loss of the gene in mice was found to protect from obesity. Later, FTO was found to encode an m6A RNA demethylase and has a profound effect on many biological and metabolic processes. In this review, we first summarize recent studies that demonstrate the critical roles and regulatory mechanisms of FTO in obesity and metabolic disease. Second, we discuss the ongoing debates concerning the association between FTO polymorphisms and obesity. Third, since several small molecule drugs and micronutrients have been found to regulate metabolic homeostasis through controlling the expression or activity of FTO, we highlight the broad potential of targeting FTO for obesity treatment. Improving our understanding of FTO and the underlying mechanisms may provide new approaches for treating obesity and metabolic diseases.

... Conclusion
... The discovery of FTO as an m6A demethylase has revealed the significance of FTO in epigenetic regulation. Developing effective inhibitors to target FTO's m6A demethylase activity or searching for plant extracts to inhibit the expression of FTO may serve as a feasible way to remedy obesity and associated diseases. Intriguingly, several small-molecule FTO inhibitors have been studied and they exhibit powerful anti-tumor effects in multiple types of cancers... In addition, entacapone, a Food and Drug Administration-approved drug, was confirmed as a potent FTO chemical inhibitor by using biochemical and structural experiments. Entacapone administration lowered fasting blood glucose concentrations and decreased body weight in diet-induced obese mice... These investigations provide evidence in targeting FTO for metabolic disorders therapy. However, considering that the ubiquitous expression of FTO and the negative phenotype in humans and mice with FTO deficiency, ,.. further explorations are needed to dig into the underlying mechanisms between FTO and metabolic diseases in-depth, which could help to develop more FTO inhibitors or/and other efficacious drugs to propel the field of epitranscriptomics forward."

Sutapa Mukherjee et al. 2017. The genetics of obstructive sleep apnea. Respirology. 2017 Nov 7;23(1):18–27. doi: 10.1111/resp.13212 . https://onlinelibrary.wiley.com/doi/10.1111/resp.13212 FREE ACCESS

... Regulation of body weight and fat distribution are genetically modulated. Recent GWAS {genome wide association study} in up to 339,224 individuals have identified 97 loci that contribute to normal variation in BMI, implicating genes and pathways related to synaptic function, glutamate signaling, insulin action and secretion, energy metabolism, lipid biology, and adipogenesis ...

Common Sweetener May Damage Critical Brain Barrier, Risking Stroke
Health
Havovi Chichger, The Conversation | 10 February 2026

"... erythritol may damage cells in the blood-brain barrier, the brain's security system that keeps out harmful substances while letting in nutrients.

The findings add troubling new detail to previous observational studies that have linked erythritol consumption to increased rates of heart attack and stroke..."

https://www.sciencealert.com/common-sweetener-may-damage-critical-brain-barrier-...
------------------------------------------------

Ion Romulus et al. 2026. Erythritol and endothelial function: interpreting in vitro findings with caution (Letter to the Editor). Journal of Applied Physiology, Volume 139, Issue 6. https://doi.org/10.1152/japplphysiol.00904.2025 https://journals.physiology.org/doi/full/10.1152/japplphysiol.00904.2025

... Berry et al. (1) provide valuable mechanistic data, but their clinical implications should be interpreted with caution. Erythritol’s unique pharmacokinetics, endogenous production, and the available human data argue against viewing it as an independent cerebrovascular toxin.
------------------------------------------------

Auburn R. Berry et al. 2026. The non-nutritive sweetener erythritol adversely affects brain microvascular endothelial cell function. Journal of Applied Physiology, Volume 138, Issue 6. https://doi.org/10.1152/japplphysiol.00276.2025 https://journals.physiology.org/doi/full/10.1152/japplphysiol.00276.2025

Eric Topol {Scripps MD scientist} ‪@erictopol.bsky.social‬ | 8:02 PM · Feb 15, 2026:

"A new systematic analysis of intermittent fasting from 22 randomized trials shows no advantage for weight loss or other outcomes compared with regular diet advice"
https://bsky.app/profile/erictopol.bsky.social/post/3mewu3l35uk2z
---------------------------------------------

Luis I Garegnani et al. 2026. Intermittent fasting for adults with overweight or obesity.
Cochrane Database of Systematic Reviews, Review - Intervention: 16 February 2026.
https://doi.org/10.1002/14651858.CD015610.pub2 https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD015610.pub2/full

ABSTRACT
"... Authors' conclusions
Compared to regular dietary advice, intermittent fasting may result in little to no difference in weight loss or quality of life. Intermittent fasting may result in little to no difference in adverse events, but the evidence is very uncertain. These approaches did not differ in achieving weight loss, producing no clinically meaningful changes in most of the outcomes considered in this review. Compared to no intervention or waiting list, intermittent fasting likely results in little to no difference in weight loss and may result in little to no difference in quality of life or adverse events, but the evidence is very uncertain.

Physicians and patients may need to evaluate willingness and readiness to implement intermittent fasting as a treatment strategy, based on individual practicality and sustainability.

The included studies focused on short‐term effects of the intervention (up to 12 months), limiting the applicability of the evidence in this review to inform decision‐making for longer durations. It would be beneficial for future studies to extend follow‐up periods beyond 12 months to build a stronger evidence base for the long‐term effects.

Further research is needed to address the effect of intermittent fasting on several outcomes, including participant satisfaction, diabetes status and overall measures of comorbidities. These studies must consider different populations where obesity and overweight have different burdens, like those from low‐ and middle‐income countries and high‐income countries, men or women separately, and different body mass index categories."

Xin Yin et al. 2026. Paternal exercise confers endurance capacity to offspring through sperm microRNAs. Cell Metabolism Volume 37, Issue 11p 2167-2184. e8November 04, 2025. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(25)00388-2 Open access

Highlights
• Paternal exercise enhances endurance capacity and metabolic health in adult offspring
• Sperm microRNAs regulate embryonic NCoR1 to transmit exercise-induced phenotypes
• Paternal exercise provides a cost-effective route to improve offspring health

https://x.com/EricTopol/status/1975218726959300789/photo/1

New Report Highlights Fructose as a Key Driver of Metabolic Disease
Kelsea Pieters | April 17, 2026

"Researchers emphasize fructose’s unique role in obesity, metabolic syndrome and other chronic diseases ..."

https://news.cuanschutz.edu/news-stories/new-report-highlights-fructose-as-a-key...
---------------------------------------------------

Johnson, R.J., Lanaspa, M.A., Tolan, D.R. et al. Fructose: metabolic signal and modern hazard. Nat Metab (2026). https://doi.org/10.1038/s42255-026-01506-y https://www.nature.com/articles/s42255-026-01506-y

Abstract
There is much interest in the role of sweeteners such as table sugar (sucrose) and high-fructose corn syrup in obesity and metabolic disease. Both sweeteners consist of glucose and fructose, two six-carbon isomeric sugars. Whereas glucose ingestion may promote obesity through its effects to stimulate insulin secretion, fructose has unique metabolic effects that promote triglyceride synthesis and fat accumulation. These effects arise from fructose’s well-known role as a signal of metabolic plenty. Under modern conditions of overnutrition, chronic excess fructose drives features of metabolic syndrome. Emerging evidence further links fructose to cancer and dementia. Here we review the biochemical, molecular and physiological distinctions between fructose and glucose, as well as the endogenous fructose pathway that makes fructose from glucose. Through this Review, we highlight the role of fructose not only as a caloric source, but also as a regulator of metabolic health and disease.

Medicare delays GLP-1 coverage plan; interim program extended
Dulan Lokuwithana | Apr 22, 2026

The Trump administration has extended a short-term program that offers Medicare coverage for weight loss drugs such as Novo’s (NVO) Wegovy and Lilly’s (LLY) Zepbound after leading health insurers balked at participating in a long-term payment model.

According to the Centers for Medicare and Medicaid Services (CMS), the interim coverage program that is scheduled to start in July will now run until the end of 2027, compared to its previous plans to end by the end of this year.

As part of the program, the agency will directly pay for the weight loss medications rather than adding them to Medicare plans and forcing health insurers to cover the expenses.

Medicare extended the interim program “after listening to stakeholder feedback,” The Wall Street Journal reported, quoting a spokeswoman from CMS. The decision will “allow data collection that will support a more effective potential implementation” of the longer-term model, she added ..."

https://seekingalpha.com/news/4577803-medicare-delays-glp-1-coverage-plan-interi...

Amazing to me how quickly we animals evolve in response to shifts in the environment - with generation times of ~20 years. Our ancestors, evolved many responses to periodic famine and other shifts in the environment (like availability of milk, sunshine). Here is yet another example ... first, is physiological response and culture, then genes?

PNAS: "The transition to farming in Neolithic Europe ~8,500 years ago caused a human population boom, but also caused reductions in average body size, suggesting a shift in life history strategies to prioritize reproduction over skeletal growth."

Eóin W. Parkinson et al. 2026. Fifteen thousand years of bioarchaeological data reveal life history trade-offs among Europe’s first farmers. PNAS April 20, 2026. 123 (17) e2505519123. https://doi.org/10.1073/pnas.2505519123 https://www.pnas.org/doi/10.1073/pnas.2505519123

William Wallace, Ph.D. 4m {May 10, 2025. Facebook}
https://www.facebook.com/williamwallacePhD

"The number on your scale is not what your brain is responding to.

A new study followed 533 adults for up to 16 years with repeated abdominal and brain MRI. Participants came from four prior dietary intervention trials at Ben-Gurion University. Researchers measured cumulative visceral fat exposure and tracked brain volume, gray matter, hippocampus structure, and cognitive scores across the entire follow-up.

People with lower cumulative visceral fat had more preserved brain volume, larger gray matter, better hippocampus structure, and higher cognitive scores in late midlife.
What did not predict brain preservation: subcutaneous fat, BMI, total weight, lipid panels, inflammatory markers. The fat just under your skin showed no association. Body weight showed no association. LDL and CRP showed no association.

One blood signal mediated the relationship between visceral fat and brain aging. Glucose control. Fasting glucose and HbA1c. Not cholesterol. Not inflammation.
The most provocative finding involves time. Visceral fat reductions during the original 18-month dietary intervention predicted better brain structure 5 to 10 years later. Even when participants regained their weight. The body composition memory outlasted the diet itself.

A few caveats. The cohort was 86% men, so generalizability to women is limited. The follow-up after randomization was observational, not interventional. MoCA is a cognitive screen, not a full neuropsychological battery.

The practical takeaway is uncomfortable for the GLP-1 era. Weight loss alone is not the brain-preserving move. Where the fat sits, and what your fasting glucose looks like over years, matter more than what the scale says on any given morning."
--------------------------------------------------------

Pachter D, et al. 2026. Sustained visceral fat loss is associated with attenuated brain atrophy and improved cognitive function in late midlife. Nature Communications, 2026. https://doi.org/10.1038/s41467-026-71141-4 Open Access

Nature Portfolio: A Review in Nature Reviews Drug Discovery outlines the current landscape of obesity drug development, focusing on GLP-1 receptor agonists, multi-receptor agonists, amylin receptor antagonists and next generation oral therapies, and also discusses the key challenges and emerging treatment concepts.
----------------------------------------------------

Jonas Petersen et al. 2026. The evolving landscape of obesity pharmacotherapy (Review). Nat Rev Drug Discov (2026). https://doi.org/10.1038/s41573-026-01427-1 https://www.nature.com/articles/s41573-026-01427-1

Online access to this article has been provided by Springer Nature SharedIt: https://www.nature.com/articles/s41573-026-01427-1.epdf?sharing_token=9rZXaME5tF...

Experimental Drug Yields Dramatic Weight Loss
AJ Mast/Bloomberg | May 21 2026

People who got the injection, retatrutide, lost 28 percent of their body weight on average after 80 weeks, Eli Lilly said ...

{Paywall } https://www.nytimes.com/2026/05/21/science/retatrutide-weight-loss-drug.html
-----------------------------------------------

People lost up to 85 pounds on Lilly’s experimental weight loss drug, company says
Berkeley Lovelace Jr. | May 21, 2026

"The results — the most weight loss ever seen in a medication trial — put the drug’s effectiveness on par with bariatric surgery.

... Lilly has not yet filed for Food and Drug Administration approval for retatrutide. It has said it expects to file for approval as early as this year.

Retatrutide is in the same class of medications as Wegovy and Zepbound, which mimic a hormone called GLP-1. Retatrutide, however, is a so-called triple agonist — in addition to GLP-1, it also mimics the hormones GIP and glucagon. (Lilly’s Zepbound, a double agonist, mimics GLP-1 and GIP.)

... Dr. Shauna Levy, medical director of the Tulane Weight Loss Center, said the current GLP-1s may not provide enough weight loss for people with severe obesity, classified as a body mass index of at least 35 ..."

https://www.nbcnews.com/health/health-news/people-lost-85-pounds-lillys-experime...

Two people can absorb different calories from the same meal
Rodielon Putol | 30 May 2026

... Participants followed one of two eating patterns.

One diet was rich in fiber and resistant starch, featuring less processed foods and larger food particles.

The other reflected a more typical Western diet with lower fiber levels and more processed foods.

People eating the Western diet absorbed about 116 more calories per day than those eating the high-fiber diet. Even so, the high-fiber group did not report feeling hungrier ...

https://www.earth.com/news/two-people-can-absorb-different-calories-from-the-sam...
---------------------------------------------

Taylor L. Davis et al. 2026. Modeling the microbial contribution to human energy balance using the Digestion, Absorption, and Microbial Metabolism (DAMM) model. PLOS One. Published: May 27, 2026. https://doi.org/10.1371/journal.pone.0347668 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0347668 OPEN ACCESS

>65 margd: You had me worried there for a second. I was afraid someone was forcing two people to eat the same meal from the same plate at the same time. :-)

Why Canada has generic Ozempic, and the US doesn't
Nadine Yousif | June 3, 2026

"... In May, Canada became the first country in the G7 to approve a generic semaglutide injection, intended for type 2 diabetes patients but can be prescribed off-label for weight loss. The discounted medications are expected to be in pharmacies across the country as of the beginning of June, at less than a third of the cost. {those not eligible for Ontario insurance drug coverage offered to diabetic seniors pay between C$350 to C$500 out of pocket}

The arrival of the generics has the potential to make GLP-1 drugs more accessible to the three million Canadians who take them, as well as to many others who have considered it but resisted because of the price. It has already forced Novo Nordisk to lower prices of their brand-name drugs.

Experts say the Canadian generics may also be eyed by patients in the US, where Ozempic costs upwards of US$1,000 per month for uninsured Americans, and where low-cost alternatives are not expected to arrive on the market for a few more years due to drug patent laws that allow companies to maintain a monopoly for longer. More than 15 million American adults are estimated to take GLP-1 medications...."

https://www.bbc.com/news/articles/c142y4p2eyxo

A.H.-C. Hsu et al. 2026. GLP-1 receptor agonist use and cancer risk in obese nondiabetic adults. Annals of Oncology, June 07, 2026. https://www.annalsofoncology.org/article/S0923-7534(26)00157-2/fulltext

ABSTRACT
"... Results. The cohort included 229 467 patients; 86 422 (37.7%) received GLP-1RAs {GLP-1 receptor agonists}, while 143 045 (62.3%) received diet or exercise consultation. ... Mean age of patients was 47.2 years ... With a median follow-up of 2 years (interquartile range 1-2 years), the propensity score matching analysis showed a significantly lower incidence of any OACs {obesity-associated cancers} among GLP-1RA users (hazard ratio 0.59 ...). Secondary analyses showed that in all subgroups, except for black race, GLP-1RA use was associated with a lower cumulative incidence of OACs. The inverse probability of treatment weighting analysis confirmed the findings.

Conclusions. GLP-1RA use was associated with a significantly lower short-term incidence of OACs among obese, nondiabetic patients, with consistent results observed in subgroups, except for race. Prospective trials are needed to confirm causality."

Wang, J., Mao, L., Yang, Y. et al. 2026 Exercise, nutrition, physical agent therapy in older adults with sarcopenic obesity: a systematic review and network meta-analysis. BMC Geriatr 26, 532 (2026). https://doi.org/10.1186/s12877-026-07207-1

ABSTRACT
Background. Sarcopenic obesity (SO) is characterized by the co-existence of excess adiposity and low muscle performance, with a high prevalence and poor prognosis in the geriatric population.
Objectives. This systematic review and network meta-analysis (NMA) aims to assess the most effective non-pharmacological interventions for SO patients, including nutrition, exercise, and physical agent therapy.
Methods. A systematic search of six electronic databases was conducted from their inception until July 5, 2025, for randomized controlled trials. The NMA utilized a random-effects model, pooled mean difference (MD) and standardized mean difference (SMD), with 95% credible intervals (CrI), accounting for correlations within multi-arm trials. Subgroup analyses and sensitivity analyses were also performed.
Results. Twenty-five studies were included, with 19 studies (n = 1,085 participants) eligible for the NMA. Interventions were categorized into 12 groups:
no intervention,
nutrition,
whole-body electromyostimulation (WBEMS),
WBEMS plus nutrition,
resistance training (RT),
aerobic training (AT),
mixed exercise (RT + AT),
mixed exercise plus nutrition,
energy restriction plus nutrition,
high-speed resistance training,
RT plus nutrition, and
electrical acupuncture plus nutrition.
Intervention duration ranged from 8 weeks to 8 months. Mixed exercise was the most effective intervention for reducing body fat percentage (BF%) (MD: -3.8, 95% CrI: -6.8, -0.8), followed by RT (MD: -2.4, 95% CrI: -4.5, -0.46). RT also significantly improved grip strength (MD: 4.4, 95% CrI: 1.6, 6.8). In the fat outcomes combined model, electrical acupuncture plus nutrition showed efficacy (MD: -2.2, 95% CrI: -3.5, -0.78). In the muscular outcomes combined model, both RT (MD: 0.36, 95% CrI: 0.14, 0.56) and RT plus nutrition (MD: 0.83, 95% CrI: 0.092, 1.7) were effective. Sensitivity analyses indicate that the models for body weight, BF%, and the two composite outcomes lack robustness.
Conclusions
RT can reduce BF% while simultaneously improving grip strength, representing an effective management strategy for SO.

... Conclusion
This NMA {review} indicates that RT {resistance training} alone is the most effective strategy for improving physical condition in SO {sarcopenic obesity} patients, as it simultaneously reduces BF% {body fat} and increases grip strength. Mixed exercise demonstrates superior efficacy than RT in reducing BF%, though neither significantly improved muscle mass nor function. The current evidence does not support the significant efficacy of any intervention for BW {body weight}, BF in kg, AFFM {appendicular fat free mass}, or gait speed, likely due to the limited number of studies available for the corresponding analyses. Nutritional support alone is not recommended for SO patients. Regarding the two outcomes combined models, electrical acupuncture plus nutrition supplements {e.g., whey protein powder and amino acid supplements} demonstrates significant fat-reducing effects, while RT alone or combined with nutrition supplements effectively improve muscle performance. However, clinical decision-making based on combined models requires caution. Comprehensive intervention protocols integrating energy restriction, RT, and protein supplementation, as well as alternative modalities such as neuromuscular electrical stimulation, retain significant potential for clinical application.

Hu Lieu et al. 2018. Butyrate: A Double-Edged Sword for Health? Advances in Nutrition Volume 9, Issue 1, January 2018, Pages 21-29. https://doi.org/10.1093/advances/nmx009 https://www.sciencedirect.com/science/article/pii/S216183132200833X?via%3Dihub

Abstract... In this review, we summarize the present knowledge on the properties of butyrate, especially its potential effects and mechanisms involved in intestinal health and obesity.

Butyrate and Obesity: Inhibition or Promotion?
... In conclusion, although a large body of evidence has suggested the effect of butyrate on alleviating high fat diet–induced obesity and insulin resistance, a few studies showed an opposite effect. Therefore, additional investigations are warranted to understand the apparently paradoxical effects of butyrate on obesity ...

Conclusions
Microbe-derived butyrate plays an important role in both gut health and obesity of the host. New mechanisms are being revealed. The reason behind the paradoxical effect of butyrate on glucose and lipid metabolism, especially with regard to its role in obesity, remains elusive. The effect of endogenous butyrate on the gut-brain axis warrants further investigations. A better understanding of the mechanism of action of butyrate in intestinal physiology and lipid metabolism will facilitate the application of butyrate and HDAC inhibitors in gut health improvement and control and the prevention of metabolic diseases.