Obesity

Analyzing data from the SURMOUNT-1 trial, the authors show that the weight loss effects of tirzepatide treatment are similar in carriers and noncarriers of MC4R pathogenic mutations.

Despite increasing availability of pharmacotherapies, interventions targeting unhealthy lifestyle behaviors continue to be critically important in the prevention and management of cardiometabolic diseases—and should be reinforced by supportive environments and policy measures.

This authoritative Perspective lays a foundation for the field of obesity research by comparing commonalities and differences between competing models of obesity pathogenesis and by defining terms that are at the core of this discussion.

Neural mechanisms underlying energy metabolism are not fully understood. Here authors show that Phf6-expressing neurons in the medial preoptic area as key regulators of physical activity and energy expenditure, revealing a neural mechanism underlying obesity in Börjeson-Forssman-Lehmann syndrome.

Maternal obesity is known to cause systemic lipid dysregulation, yet its effect on lipid reprogramming during the maternal-to-zygotic transition (MZT) remains unknown. Here, they show that obesity disrupts very-long-chain fatty acids (VLCFAs) storage in oocytes, impairing peroxisomal protein import in 2-cell embryos.

This study found that obesity increases the stress protein REDD1, which drives vascular ageing and high blood pressure. REDD1 activates an atypical NF-κB signaling pathway and microRNAs that switch off genes protecting blood vessels. Blocking this pathway improves vascular and kidney function in obese mice, highlighting a potential therapeutic target.

Knaan et al. examine metabolic and behavioral adaptations to a 12-week supervised aerobic exercise program in adults with overweight. Exercise induces energy compensation through reduced resting metabolism, improved movement efficiency, and selective shrinkage of highly metabolic organs, thereby limiting weight loss.

Environmental and pharmaceutical compounds induce an obesogenic thrifty phenotype in zebrafish under short-term fasting conditions, which are related neither to locomotor activity changes nor to food consumption.

Yue et al. use machine learning to identify brain connectivity patterns distinguishing individuals with and without obesity across metabolic states. Six key connectivity features classify obesity with 95% accuracy, revealing reduced communication in food-reward regions and a central role of the dorsal anterior cingulate cortex.

Novel treatments are needed for type 2 diabetes mellitus which target insulin resistance, lipid metabolism dysregulation, and gut microbiome dysbiosis. Here the authors engineered a probiotic to tolerate oxidative stress, an alleviate type 2 diabetes in mice by activating host metabolic pathways.

Endocrine-exocrine pancreas crosstalk is known to play a role in pancreatic ductal adenocarcinoma. Here, the authors discover that obesity induces the expression of the peptide hormone cholecystokinin (CCK) in β cells, affecting the peri-islet acinar cells and promoting islet-proximal tumor formation.

Paternal obesity impacts offspring health, though the underlying mechanisms remain poorly understood. Here, the authors show that male obesity drives adipose mitochondrial dysfunction in F₁ mouse progeny via a let-7-DICER axis, identifying a pathway for intergenerational metabolic inheritance

Age-related obesity is a major health issue with unclear causes. This work reveals that the enzyme GSNOR promotes obesity by reducing mitochondria in fat, leading to tissue “whitening” and identifying it as a potential therapeutic target.

Here the authors report that intestinal interleukin-22 promotes GLP-1 production through STAT3 signaling in male mice. This mechanism improves glucose regulation in diet-induced obesity and provides insight into the role of IL-22–GLP-1 signaling in metabolic regulation.

The mediobasal hypothalamus plays a central role in integrating nutritional and sex-related signals to regulate energy homeostasis. Here, through snRNA-seq of the mediobasal hypothalamus in female and male mice across nutritional states, authors show that Agrp neurons are nutrition-sensitive, DA neurons exhibit transcriptional differences in a sex-dependent manner, and KNDy neurons are responsive to both sex and nutrition.

How leptin signalling produces anti‑obesity effects is incompletely understood. Here, the authors demonstrate that FAK and PYK2 are required for STAT3 activation, normal leptin responses, and HDAC6 inhibitor‑mediated weight loss, with their loss causing hyperphagic obesity.

Obesity impairs metabolic flexibility-the capacity to adapt to fluctuating energy demands. Here, authors show that PRMT3 mediates the post-translational adaptation of visceral fat to fasting regulates metabolic flexibility and could be a therapeutic target for obesity.

A high fat diet increases liver-derived miR-122-5p in circulating exosomes, which induces Leydig cell ferroptosis by downregulating Scd2, leading to decreased testosterone synthesis and abnormal spermatogenesis.

This study identifies protein signatures of pediatric obesity linked to cardiometabolic risk, shows treatment-related changes, and highlights a three-protein panel predictive of steatotic liver disease for early diagnosis

How high-fat diet disrupts brain circuits that regulate food intake is unclear. Here, the authors show such a diet downregulates Hcn1 and Gad2 in lateral septum, which in turn disrupts circuit activity and promotes overeating and obesity in mice.

“This randomized controlled trial in adults with central obesity found that high-intensity interval training, performed once or thrice weekly, reduced body fat mass compared with control, highlighting the benefits of “weekend warrior” interventions.”

The global burden of Metabolic syndrome is incompletely characterized. Here the authors report a systematic review and modelling study showing that global metabolic syndrome prevalence doubled from 2000 to 2023, now affecting 1.54 billion adults (31.0% of women, 25.7% of men), with higher rates in women, urban areas, and high-income countries, with disparities across regions.

Intestinal mucin 1 (MUC1) is a glycosylated protein that maintains intestinal epithelial barrier (IEB) integrity. Here, the authors show that reduced intestinal MUC1 levels and glycosylation facilitate metabolic dysfunction-associated steatotic liver disease (MASLD) progression by impairing IEB integrity, via clathrin-mediated endocytosis and NEDD4-mediated lysosomal degradation of MUC1 (triggered by decreased glycosylation).

Shi, Yu et al. examine the associations of abdominal obesity and plasma fatty acids with microvascular diseases risk in the UK Biobank cohort. Authors find that n-3 polyunsaturated fatty acids are associated with a lower risk, whereas saturated- and monounsaturated- fatty acids are associated with an increased risk.

Poyraz, Heinonen et al. model the individual postprandial glucose and insulin responses in people with obesity who underwent either Roux-en-Y gastric bypass or One-Anastomosis gastric bypass surgery. They find differences in postprandial glucose and insulin responses related to the surgery method used.

Wang et al. examine the sex-specific associations of intrapancreatic fat deposition (IPFD) with incident type 2 diabetes (T2D) using the UK biobank cohort. IPFD is associated with incident T2D independent of BMI, hepatic fat and visceral fat in men and independent of BMI and hepatic fat in women.

Riedel et al. follow up children with obesity when they become young adults. Although obesity persists in most cases with serious complications already present, most participants do not accurately perceive their health burden and have lost contact with the healthcare system.

Maternal obesogenic diet exposure alters offspring bile acid metabolism and gut immune development with associated worsening of fibroinflammatory liver disease. Bile acids may play a critical role in programming gut immune cell populations.

Obesity alters the transcriptome profile of adipose-tissue derived mesenchymal stem cells (ASCs) and impairs ciliary biogenesis. Restoring adenylate cyclase 3 activity partially rescues ciliary integrity and function of ASCs from donors with obesity.

Biobank-scale cross-ancestry analysis identifies previously unreported obesity genes and reveals ancestry-specific effects, combined rare–common variant impact, downstream protein mediators, and risks to cardiometabolic comorbidities.

A systematic review and meta-analysis of clinical trials investigating the efficacy and safety of obesity management medications reported tirzepatide and semaglutide to be the most effective in reducing body weight and obesity-related complications.

In an observational study comparing individuals with type 2 diabetes and obesity who underwent metabolic surgery with similar individuals who received GLP-1 receptor agonist treatment, metabolic surgery was associated with a lower risk of macrovascular and microvascular outcomes, including major adverse cardiovascular events, nephropathy, retinopathy and all-cause mortality.

A free-living trial in people with overweight or obesity found that minimally processed diets led to greater weight loss and cardiometabolic improvements than ultraprocessed diets following UK healthy eating guidelines at 8 weeks.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

In a 6-week randomized phase 1 trial, tirzepatide led to reduced caloric intake during a meal test at week 3 compared with placebo and liraglutide in people with overweight or obesity.

A reinforcement learning-based virtual reality system, implementing a series of sport sessions with coaching, was as effective as standard physical activity in reducing fat mass in adolescents, with positive effects on cognition.

The authors found, after analyzing 10,960 individuals from 9 multiancestry biobanks across 6 countries, that genetic factors previously associated with BMI have limited impact on GLP-1 receptor agonist-induced weight loss.

A randomized clinical trial showing the superiority of behavioral treatment plus phentermine to behavioral treatment plus placebo for weight loss in those that previously had not responded to behavioral treatment.

Simultaneous PET-MRI measurements provide fundamental insights into the modulation of neural networks mediated by nicotinic acetylcholine receptors in human obesity as a putative biological mechanism for future weight loss interventions.

The role of lysine crotonylation (Kcr) in MASLD pathogenesis remains unclear. Here, the authors identify a PCAF/SIRT7-IDH1 Kcr axis that ameliorates hepatic steatosis by boosting TCA cycle activity, uncovering a new mechanism and therapeutic target for MASLD.

Huang et al. analyze matched adults with obesity receiving Tirzepatide, Semaglutide, Phentermine/Topiramate, Naltrexone/Bupropion, or Phentermine monotherapy. Iirzepatide mirrors semaglutide for ocular safety, while both drugs link to fewer cataracts, oculomotor dysfunction, and visual issues than phentermine or naltrexone/bupropion.

Hirose et al. demonstrate a genome editing-based strategy to treat obesity and pre-diabetes, complex diseases without a defined genetic cause. A single in vivo knock-in of a secretion-engineered Exendin-4 gene into the liver enables sustained peptide release, reducing body weight and improving glucose metabolism in mice.

Obesity leads to pathological expansion of white adipose tissue driving vascular dysfunction. Here, the authors utilize single-cell RNA sequencing to elucidate endothelial heterogeneity and demarcate key differences in obesity-associated vascular alterations in subcutaneous and visceral white adipose tissue.

This study, together with a companion manuscript, shows that in mice, weight loss as a result of GIP receptor antagonism requires and potentiates functional GLP-1 receptor signalling in the brain, explaining how both GIP receptor agonists and antagonists trigger weight loss through different mechanisms.

This study, together with a companion manuscript, show that, in mice, weight loss as a result of GIP receptor antagonism requires, and potentiates, functional GLP-1 receptor signalling in the brain, explaining how both GIP receptor agonists and antagonists trigger weight loss through different mechanisms.

Epigenome association study of father’s preconception body silhouette with offspring DNA methylation, providing mechanistic insight into how epigenetic inheritance impacts offspring obesity, asthma and lung function.

Sellers, van Beek and colleagues show that intermittent cold exposure for 10 days, which induced 1 h of shivering per day, improves glucose homeostasis, lipid metabolism and blood pressure in adults with overweight or obesity.

Standardized indices of obesity are associated with alterations in neural oscillatory activity and functional connectivity in brain regions supporting abstract reasoning and fluid intelligence in typically developing youth.

Zhou et al. reveal that rhein improves adipose tissue thermogenesis via suppressing the NLRP3 inflammasome in macrophages during obesity. They further identify that rhein directly binds to SIRT2 and inhibits NLRP3 inflammasome by activating SIRT2.

Changes in lipidome profiles, as reflected by improvements in dietary fat quality from saturated to unsaturated fats, were associated with reduced cardiometabolic disease risk, and high-risk populations with unhealthy lipidome profiles would most benefit from an olive oil-rich Mediterranean diet.

Somani, Jain et al. evaluate public perceptions of glucagon-like peptide-1 receptor agonists with large language model-based analysis of social media posts. Sentiments were neutral-to-positive, and discussions included use in weight loss, side effects, and issues with access and supply.

In a prespecified analysis of the FLOW trial, the use of an SGLT2 inhibitor did not impact the overall benefits of semaglutide on kidney and cardiovascular outcomes in participants with type 2 diabetes and chronic kidney disease.

Veniant et al. report here on a GIPR antagonist conjugated to GLP-1 analogues that reduces body weight and improves metabolic markers in preclinical and phase 1 clinical settings.

Skeletal muscle aging is characterized by the loss of muscle mass and function, mainly attributed to the atrophy of glycolytic fibers. The underlying mechanisms driving this impairment were investigated in unbiased approaches in a glycolytic muscle.

Wang et al. use Mendelian randomization to study the causal interaction between physical activity, education, and BMI, finding that more physical activity leads to a lower BMI, while sedentary behavior is a consequence of higher BMI. More years of schooling encourages higher physical activity and lower BMI, emphasizing its positive impact on health.