bims-obesme 2026-08-09 papers

Issue of 2026–08–09
three papers selected by
Xiong Weng, University of Edinburgh

Sci Adv. 2026 Aug 07. 12(32): eaed5600

Skeletal muscle H3K18 lactylation inhibits hepatic gluconeogenesis through IL-6 mediated interorgan communication.

Yu Wang, Feijie Wang, Yujie Sun, Yao Gu, Lamei Xue, Mingcong Fan, Haifeng Qian, Yucheng Wang, Hao Ying, Jun Du, Liang Chen, Li Wang, Yan Li.

The mechanisms underlying the dynamic interplay between skeletal muscle and systemic glucose homeostasis in type 2 diabetes remain elusive. Increased lactate level has long been noticed in diabetes, however, whether the elevated lactate is a cause or consequence of impaired glucose metabolism is unclear. Here, we found that elevated circulating lactate levels originated from skeletal muscle with high expression of lactate dehydrogenase A (Ldha), and both metrics correlated strongly with hyperglycemia in both hyperglycemic mouse models and human subjects. Paradoxically, ablation of Ldha in skeletal muscle (LDHA mKO) disrupted whole-body glucose homeostasis, primarily via augmented hepatic gluconeogenesis. Mechanistically, lactate deficiency in muscle epigenetically activated NF-κB signaling through H3K18 lactylation (H3K18la)-mediated transcriptional control of IκBα, which then promoted the transcription of IL-6, thereby reshaping hepatic gluconeogenesis. Lastly, we showed that loss of Ldha in skeletal muscle enhanced hepatic gluconeogenesis and aggravated hyperglycemia in high-fat high-sucrose diet-fed mice. Collectively, our study provides evidence that in glucose intoxication contexts, skeletal muscle-derived lactate acts as the signal to provide negative feedback for hepatic gluconeogenesis, which induces skeletal muscle H3K18la acting as a negative regulator of IL-6 to sustain suppression of hepatic gluconeogenesis, while dysregulation of this network contributes to unrestrained gluconeogenesis in diabetes.

DOI: https://doi.org/10.1126/sciadv.aed5600

Metabolism. 2026 Aug 05. pii: S0026-0495(26)00242-8. [Epub ahead of print] 156729

Adipocyte caspase-1 deficiency promotes white fat beiging via COX7A2L-dependent mitochondrial respiration.

Yumeng Wang, Jiajie Li, Weijiong He, Furong Zhao, Yunzi Kang, Yewei Cui, Hongxiang Zeng, Ting Zeng, Rui Cheng, Shujin Wang, Linqiang Zhang, Rui Wang, Xueya Zhao, Liuling Xiao, Xi Li.

Beiging of white adipose tissue (WAT) is a promising strategy to enhance energy expenditure and combat obesity, a growing global health burden. Here, we identify a non-canonical role of caspase-1, a cysteine protease, in regulating adipocyte thermogenesis. Caspase-1 expression in adipocytes of inguinal WAT is downregulated upon cold exposure but elevated in obesity. Adipocyte-specific caspase-1 deficiency promotes WAT beiging, increases whole-body energy expenditure, and ameliorates high-fat diet-induced obesity and metabolic dysfunction. Mechanistically, cAMP signaling suppresses Casp1 transcription via C/EBPβ. Proteomic and functional analyses reveal that caspase-1 interacts with and modulates the protein levels of COX7A2L, a subunit of mitochondrial complex IV. Loss of Casp1 stabilizes COX7A2L, thereby enhancing mitochondrial respiration. Moreover, CASP1 expression in human WAT significantly increases with obesity and metabolic dysfunction. Accordingly, we developed a sustained-release delivery system for the caspase-1 inhibitor Ac-YVAD-CHO, which effectively protects against diet-induced obesity and improves glucose tolerance in mice. These findings reveal a previously unrecognized inflammation-independent role of adipocyte-intrinsic caspase-1 in adipose beiging and highlight caspase-1 as a potential therapeutic target for obesity.

Keywords: Adipocyte; COX7A2L; Caspase-1; Metabolic homeostasis; White fat beiging

DOI: https://doi.org/10.1016/j.metabol.2026.156729

Nature. 2026 Aug 05.

FNIP1 variants are associated with favourable metabolism in 1 million humans.

Regeneron Genetics Center

Altered energy metabolism is a shared driver across cardiometabolic diseases-the leading cause of death globally1. Energy metabolism varies between individuals and is partly heritable2-9. Here, to investigate the genetic basis of energy metabolism, we perform an exome-sequencing analysis of 1,032,116 people from America, Europe and Asia, and estimate associations between rare protein-coding variants and the ratio of triglyceride to high-density-lipoprotein cholesterol (TG:HDL)-an energy-state biomarker that we associate with diverse cardiometabolic risk factors and diseases. We identify 59 independent genes (P < 1.04 × 10-7) that are enriched for liver- and adipose-expressed master regulators of energy balance, storage and metabolism; 23 (39%) of these genes encode approved or clinical-stage drug targets. Ultra-rare protein-truncating variants in FNIP1 (allele frequency, 0.01%), which encodes a suppressor of energy expenditure and mitochondrial metabolism, are associated with a lower TG:HDL ratio, lower liver fat, lower glycaemia, favourable fat distribution and around 60% lower odds of cardiometabolic disease. FNIP1 knockdown in primary human hepatocytes induces lipid breakdown and lysosomal gene expression, while combined hepatic knockdown of Fnip1 with its paralogue Fnip2 or knockdown of its interactor Flcn protect against weight gain, reduce liver fat and enhance insulin sensitivity in mice fed a high-fat diet. Our study implicates the FNIP1 pathway in human energy metabolism and highlights its inhibition as a potential therapeutic strategy in cardiometabolic disease.

DOI: https://doi.org/10.1038/s41586-026-10864-2