bims-obesme 2026-05-31 papers

Issue of 2026–05–31
five papers selected by
Xiong Weng, University of Edinburgh

Nat Commun. 2026 May 29.

Evaluating confounding in rare variant genome wide association studies.

Aimee L Hanson, Gareth J Griffith, Si Fang, Neil M Davies, George Davey Smith, Daniel J Lawson, Gibran Hemani.

The theorised risk that confounded rare variant associations will emerge from population based genetic studies has not been investigated empirically. Here, we use 306,991 sequenced exomes from the UK Biobank to demonstrate that recent demography is poorly captured by common and rare variant principal components, and accounting for haplotype sharing does not eliminate false-positive rare variant associations with non-heritable spatially structured traits. Through re-analysis of 155 phenotypes in siblings, we show a trend of higher effect estimates bias for non-uniformly distributed traits, suggesting population stratification is most pervasive in these settings. Despite its spatial structure, bias of rare variant associations with height appeared most strongly influenced by assortative mating. We explore the risk of elevated false discovery rates for recent variants private to extended families sharing polygenic liability to extreme phenotypes, as well as through local linkage with common causal variants. Overall, we consider the complex confounding mechanisms that can impact rare variant studies and demonstrate family-based approaches can enable important sensitivity analyses.

DOI: https://doi.org/10.1038/s41467-026-73776-9

Metabolism. 2026 May 28. pii: S0026-0495(26)00164-2. [Epub ahead of print] 156654

Hepatic TGFβ1 signaling impairs insulin sensitivity via inducing insulin receptor substrate 1 degradation.

Weiqi Ai, Quan Pan, Zheng Shen, Wanbao Yang, Wen Jiang, Jianxun Song, Shaodong Guo.

AIMS/HYPOTHESIS: Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes (T2D), yet the underlying mechanisms remain incompletely defined. We hypothesized that elevated transforming growth factor beta 1 (TGFβ1) level is associated with impaired insulin sensitivity.
METHODS: Using primary hepatocytes, and mouse models with hepatic TGFβ1 overexpression or hepatic TGFβ1 signaling disruption, we examined the impact of TGFβ1 signaling on hepatic insulin signaling and glucose metabolism. We performed bulk RNA sequencing of liver samples identify potential mediator of obesity-induced insulin resistance. Immunoprecipitation, in vitro kinase assay, and mass-spec assay were used to explore the mechanisms underlying TGFβ1-induced insulin receptor substrate (IRS1) degradation. We further evaluated the therapeutic potential of targeting TGFβ1 signaling to improve glycemic control using the TGFβ1 signaling inhibitor LY2157299.
RESULTS: Prolonged TGFβ1 exposure markedly reduced IRS1 protein abundance and impaired insulin-stimulated Akt activation in hepatocytes. Hepatic TGFβ1 overexpression exacerbated insulin resistance, whereas hepatic TGFβ1 signaling disruption improved insulin sensitivity by increasing IRS1 protein abundance. Mechanistically, TGFβ1 signaling increased Cullin 7 (CUL7) expression and promoted IRS1 phosphorylation at serine 685, leading to ubiquitin-dependent IRS1 degradation. Pharmacological inhibition of TGFβ1 signaling by LY2157299 improved insulin sensitivity in both lean and diabetic db/db mice.
CONCLUSIONS/INTERPRETATION: These findings identify TGFβ1 as a key driver of hepatic insulin resistance by promoting CUL7-dependent IRS1 degradation, establishing a mechanistic link between obesity-associated cytokine signaling and impaired insulin action and highlighting the TGFβ1-CUL7-IRS1 axis as a potential therapeutic target for T2D.

Keywords: Cullin 7 (CUL7); Insulin receptor substrate 1 (IRS1); Insulin sensitivity; Transforming growth factor beta 1 (TGFβ1)

DOI: https://doi.org/10.1016/j.metabol.2026.156654

Cell Metab. 2026 May 28. pii: S1550-4131(26)00187-7. [Epub ahead of print]

Pro-aging effects of chronic glucocorticoid signaling.

Flavia Lambertucci, Frederic Castinetti, Isabelle Martins, Carlos López-Otín, Guido Kroemer.

Glucocorticoids (GCs) are essential endocrine regulators coordinating stress responsiveness, metabolic flexibility, inflammatory resolution, and circadian physiology. While acute GC fluctuations are adaptive, sustained exposure (arising from psychosocial stress, circadian disruption, obesity, chronic inflammation, neoplasms, or steroid therapy) elicits pleiotropic effects that overlap with biological aging. Prolonged GC signaling intersects with multiple hallmarks of aging by altering nutrient sensing, suppressing autophagy, impairing mitochondrial quality control, and promoting cellular senescence. In this context, the GC-responsive polypeptide ACBP/DBI (acyl-coenzyme A [CoA]-binding protein/diazepam-binding inhibitor) has emerged as a stress-induced inhibitor of macroautophagy that amplifies several metabolic and immune consequences of GC excess linked to aging phenotypes. Clinically, chronic GC elevation is associated with earlier and more severe manifestations of age-related diseases, including metabolic syndrome, osteoporosis, sarcopenia, neurodegeneration, cardiovascular disease, immunosenescence, and cancer. Here, we review mechanistic links between GC signaling and systemic aging and discuss strategies to mitigate the age-accelerating consequences of persistent GC exposure.

Keywords: Cushing syndrome; corticosteroid; hallmarks of aging; hypercortisolism; multimorbidity; neuroendocrine system

DOI: https://doi.org/10.1016/j.cmet.2026.05.002

Cell Discov. 2026 May 26. pii: 37. [Epub ahead of print]12(1):

WAT-to-BAT communication facilitates the sustained activation of BAT thermogenesis during cold exposure.

Jieyuan Xue, Ding Chen, Chenfeng Wang, Jue Wang, Jiayu Zhou, Wenyan Li, Junxi Qian, Yuanji Huang, Liang Fang, Hongyong Song, Ben He, Xu-Yun Zhao.

The activation of brown adipose tissue (BAT) for thermogenesis represents a crucial physiological mechanism that helps maintain body temperature during cold exposure. Nevertheless, the exact mechanisms underlying the sustained activation of BAT under cold conditions remain incompletely understood. In this study, we reveal that soluble ST2 (sST2) mediates a white adipose tissue (WAT)-to-BAT endocrine mechanism that is essential for the continuous activation of BAT during cold exposure. Specific depletion of sST2 blocks alternative thermogenesis following BAT denervation and renders mice sensitive to cold during prolonged cold exposure. Mechanistically, sST2 is induced and secreted from epididymal white adipose tissue (eWAT) upon the activation of Creb1, which is driven by β1 and β2 adrenergic receptor signaling. Secreted sST2 directly binds to the β3 adrenergic receptor in BAT and, in synergy with norepinephrine, induces BAT thermogenesis independent of IL33. Additionally, supplementation with sST2 promotes beige fat formation. Therefore, our study illustrates a novel mechanism through which the adipokine sST2 derived from eWAT mediates sustained BAT activation during cold exposure through the integration of neural and humoral signals. More importantly, sST2 exerts a synergistic effect on BAT activation when combined with β3-adrenergic receptor agonists.

DOI: https://doi.org/10.1038/s41421-026-00891-8

Nat Commun. 2026 May 29. pii: 4808. [Epub ahead of print]17(1):

Dual activation of MC3R and MC4R drives weight loss and reduces food intake in male primates with obesity.

Jillian L Seiler, Anna C Impastato, Emma Xiaoyu Zhang, Kade J Kelley, Thomas L Bennett, Bradley Studnitzer, Claudia R Prindle, Benjamin H Rajewski, Barry A Badeau, Xinjian Jiang, Russell Potterfield, Jordan Y Delev, Daniel L Marks.

The melanocortin system plays a central role in regulating hunger and satiety, making it an attractive target for treating metabolic disease. However, the limited clinical success of selective melanocortin-4 receptor (MC4R) agonists has prompted investigation into whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation may more effectively engage this pathway for the treatment of general obesity. Here we show that selective MC3R agonism modulates food intake in a state-dependent manner, and that co-agonism of MC3R and MC4R produces greater metabolic effects than selective MC4R agonism alone, consistent with non-redundant and cooperative roles. Using novel peptides in male nonhuman primates and rodents, we develop 710GO, an orally available MC3R/MC4R dual agonist that induces significant weight loss in primates with diet-induced obesity. Oral 710GO demonstrates limited weight rebound, compatibility with GLP-1-based therapies, and a favorable preclinical safety profile. These findings support combined MC3R/MC4R agonism as a promising approach for next-generation obesity therapeutics.

DOI: https://doi.org/10.1038/s41467-026-73372-x