"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...