Obesity

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.

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.