bims-obesme 2026-05-10 papers

Issue of 2026–05–10
six papers selected by
Xiong Weng, University of Edinburgh

Sci Adv. 2026 May 08. 12(19): eaec0795

Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.

The maintenance of skeletal muscle mass relies on mitochondrial quality control, including balanced dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a central mediator of mitochondrial fission, is essential for these processes, yet its role in muscle mass regulation remains incompletely defined. Here, we show that acute Drp1 deletion in the skeletal muscle increases Parkin-mediated mitochondrial degradation, reduces mitochondrial DNA (mtDNA) content, and leads to severe muscle atrophy. Although dual deletion of Drp1 and Parkin restores mtDNA content, muscle loss persists. Mechanistically, Drp1 loss impairs mitochondrial respiratory chain activity, suppressing extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and down-regulating the nuclear receptor subfamily 4 group A member 1 (Nur77). Pharmacologic β2-adrenergic receptor activation with clenbuterol reactivated Erk1/2, restored Nur77 expression, and rescued muscle atrophy. These findings define a Drp1-Erk1/2-Nur77 signaling axis linking mitochondrial integrity to skeletal muscle mass and identify a potential therapeutic target for muscle degeneration in mitochondrial and metabolic diseases.

DOI: https://doi.org/10.1126/sciadv.aec0795

Cell Metab. 2026 May 07. pii: S1550-4131(26)00141-5. [Epub ahead of print]

Muscle-derived Mimecan regulates hypothalamus-brown adipose tissue communication and promotes health and lifespan in mice.

Kentaro Mori, Shin-Ichiro Imai.

Inter-organ communication plays a critical role in mammalian aging and longevity control. Here, we identified Mimecan from transcriptomic comparisons between young and aged skeletal muscles. Skeletal muscle-derived Mimecan regulates core body temperature via brown adipose tissue (BAT), which is impaired in aged mice. Skeletal muscle-specific loss- and gain-of-function models demonstrate that Mimecan activates melanocortin 4 receptor (MC4R)-positive neurons in the dorsomedial hypothalamus (DMH) and dorsal hypothalamic area (DHA) via maintaining primary cilia in those neurons, enhancing the sympathetic nervous tone directed to BAT. Furthermore, DMH/DHA-specific Mc4r-knockdown completely abolishes the effect of Mimecan overexpression on BAT function. Lastly, the restoration of Mimecan levels in blood circulation significantly extends lifespan in aged mice, suggesting that Mimecan plays a critical role in counteracting aging and promoting lifespan. Taken together, this study demonstrates the importance of inter-organ communication between the hypothalamus, skeletal muscle, and BAT in the systemic regulation of mammalian aging and longevity.

Keywords: MC4R; Mimecan; aging; brown adipose tissue; core body temperature; hypothalamus; longevity; melanocortin 4 receptor; skeletal-muscle-derived factor; sympathetic nervous system

DOI: https://doi.org/10.1016/j.cmet.2026.04.003

JCI Insight. 2026 May 08. pii: e200168. [Epub ahead of print]11(9):

A nutrient-responsive AMPK/TBK1 circuit restricts adipocyte catabolism.

Churaibhon Wisessaowapak, Yuliya Skorobogatko, Hyeonhui Kim, Xue Feng, Seunghwan Son, Haipeng Fu, Sitao Zhang, Pichaya Lertvilai, Lina Chang, Annie Hoang, Hetty Chen, Sarah Bedsted, Joseph Valentine, Jin Young Huh, Peng Zhao, Shannon M Reilly, Piyajit Watcharasit, Maryam Ahmadian, Alan R Saltiel.

Metabolic adaptation to both caloric excess and restriction promotes energy conservation by suppressing catabolic pathways via feedback mechanisms that remain incompletely defined. We identified TANK binding kinase 1 (TBK1) as a nutrient- and inflammation-responsive brake on AMPK signaling in adipocytes. Fasting or pharmacological AMPK activation induced Tbk1 transcription via a PGC1α/nuclear respiratory factor 1 axis, which, in turn, limited AMPK activity through a phosphorylation cascade to conserve energy. In obesity, this AMPK/TBK1 axis was disrupted due to chronically elevated basal TBK1, thereby restricting energy expenditure during fasting. Adipocyte-specific TBK1 deletion enhanced fasting-induced AMPK activation, mitochondrial function, and lipolytic gene expression in both lean and obese mice. Pharmacological TBK1 inhibition with amlexanox recapitulated these effects. Combined treatment of mice with amlexanox and the AMPK activator AICAR enhanced weight loss, improved glucose tolerance and insulin sensitivity, and suppressed inflammatory and lipogenic programs in adipose tissue, as well as fibrotic gene expression in the liver. Building on prior clinical observations linking TBK1 inhibition to metabolic health, these findings defined a nutrient-sensitive AMPK/TBK1 feedback loop that limited adipocyte catabolism and suggested that dual targeting of TBK1 and AMPK may help counteract metabolic adaptation and enhance the durability of obesity therapies.

Keywords: Adipose tissue; Endocrinology; Metabolism; Obesity

DOI: https://doi.org/10.1172/jci.insight.200168

Sci Adv. 2026 May 08. 12(19): eaed0535

Integrated analysis of insulin resistance reveals metabolic remodeling following diet switch-triggered calorie reduction.

Xiaowen Duan, Lucy M Davis, Satish Patel, Guillaume Bidault, Lu Long, Benjamin Jenkins, Yao Yi, Pushpa Pushpa, Julia R Wesseling, Albert Koulman, Antonio Vidal-Puig, Daniel J Fazakerley, David B Savage.

Insulin resistance (IR) links obesity to metabolic disorders. While weight loss reverses IR, we show that calorie reduction (CR) can do so in obese mice within a day before significant weight loss. In contrast to whole-body IR, individual tissues do not revert to their original chow diet-fed states after CR. In the liver, improved insulin sensitivity correlates with reduced triacylglycerol and diacylglycerol and protein kinase C epsilon activity, alongside substantially decreased de novo lipogenesis and increased ketones. In muscle, insulin-sensitive glucose disposal was restored, whereas obesity-associated adipose tissue changes largely persisted following CR, specifically the reduction in fasting lipolytic activity mediated at least, in part, by lower β-adrenergic receptor 3 expression. This, combined with enhanced oxidative pathways in muscle and liver, resulted in lowered plasma free fatty acid levels and muscle and liver lipids, facilitating insulin-stimulated glucose disposal and thus restored insulin sensitivity.

DOI: https://doi.org/10.1126/sciadv.aed0535

Cell Metab. 2026 May 07. pii: S1550-4131(26)00147-6. [Epub ahead of print]

Harnessing PPAR pharmacology through dual incretin-directed delivery.

Jonas Petersen, Christoffer Clemmensen.

In Nature, Liskiewicz et al.1 describe a unimolecular conjugate that combines GLP-1R/GIPR co-agonism with pan-PPAR nuclear hormone receptor activation, yielding a quintuple receptor agonist that links incretin signaling to PPAR-mediated transcriptional control within a single therapeutic scaffold.

DOI: https://doi.org/10.1016/j.cmet.2026.04.009

Cell Metab. 2026 May 07. pii: S1550-4131(26)00144-0. [Epub ahead of print]

Garlic-derived metabolite activates LKB1, promotes adipose eNAMPT secretion, and improves age-related muscle function via hypothalamic signaling.

Jun-Ichiro Suzuki, Kiyoshi Yoshioka, Masahiro Kurita, Takumi Sugimoto, Takahiro Eguchi, Naoki Ito, Aoi Kodama, Yasutomi Kamei, Masahiro Ohtani, Toshiaki Matsutomo, Shin-Ichiro Imai.

Garlic (Allium sativum L.) and its aged extract contain many bioactive compounds that can bring health benefits to humans. Among them, S-1-propenyl-L-cysteine (S1PC) has recently drawn significant attention in the field of nutriceutical research. However, the mechanism of its molecular action has remained poorly understood. Here, we show that S1PC significantly activates liver kinase B1 (LKB1) through enhancing its tertiary complex formation with STRAD and MO25, leading to stimulating the phosphorylation of a mammalian NAD+-dependent protein deacetylase, SIRT1, and promoting the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in white adipose tissue (WAT). Interestingly, eNAMPT secreted from WAT specifically targets the hypothalamus, significantly enhancing skeletal muscle force and improving frailty indices in aged mice. Furthermore, S1PC is also able to increase circulating eNAMPT levels in human individuals who maintain healthy adipose mass. These findings demonstrate that S1PC specifically stimulates the LKB1-SIRT1 pathway and enhances eNAMPT secretion in WAT, counteracting skeletal muscle aging in aged individuals.

Keywords: LKB1; S-1-propenyl-L-cysteine; SIRT1; aging; garlic; hypothalamus; liver kinase B1; phosphorylation; skeletal muscle; white adipose tissue

DOI: https://doi.org/10.1016/j.cmet.2026.04.006