bims-obesme 2026-02-22 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2026–02–22
six papers selected by
Xiong Weng, University of Edinburgh

Adipocyte NADH dehydrogenase reverses circadian and diet-induced metabolic syndrome.
Insulin and adipocyte IRF4 promote fat retention over muscle preservation during intermittent fasting in obesity.
Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
Hyperglutaminolysis drives senescence and aging through arginine-mTORC1 axis activation.
Structural insight into hierarchical DNMT3A autoinhibition and its dysregulation in disease.
Visceral adiposity, metabolic health and aging.

Nat Metab. 2026 Feb 18.

Adipocyte NADH dehydrogenase reverses circadian and diet-induced metabolic syndrome.

Chelsea Hepler, Nathan J Waldeck, Benjamin J Weidemann, Biliana Marcheva, You-Jia Chen, Jacqueline Hecker, Ziming Zhu, Rino Nozawa, Joseph V Mastroni, Anneke K Thorne, Colleen R Reczek, Jonathan Cedernaes, Kathryn M Ramsey, Clara B Peek, Grant D Barish, Navdeep S Chandel, Joseph Bass.

Circadian clocks are internal timing systems that enable organisms to anticipate and adapt to daily environmental changes. These rhythms arise from a transcription-translation feedback loop in which CLOCK and BMAL1 regulate the expression of thousands of genes, including their repressors PER and CRY. Disruption of circadian rhythms contributes to obesity, metabolic disease and cancer, yet how the clock maintains metabolic homeostasis remains limited. Here we report that the clock regulates oxidative metabolism in adipocytes through diurnal complex I respiration. Disrupting the clock in male mice via adipocyte-specific genetic deletion or high-fat-diet feeding reduces complex I respiration in adipocytes, leading to suppression of the peroxisome proliferator-activated receptor and insulin signalling pathways. In contrast, restoring complex I function by expressing yeast NDI1 in adipocytes protects against diet-induced and circadian-induced metabolic dysfunction independently of weight gain. These findings reveal that adipocyte circadian disruption impairs metabolic health through mitochondrial complex I dysfunction, establishing clock control of complex I as a key regulator of metabolic homeostasis.

DOI: https://doi.org/10.1038/s42255-026-01464-5
Cell Rep. 2026 Feb 19. pii: S2211-1247(26)00101-4. [Epub ahead of print]45(3): 117023

Insulin and adipocyte IRF4 promote fat retention over muscle preservation during intermittent fasting in obesity.

Daniel M Marko, Meghan O Conn, Joseph F Cavallari, Helena Neudorf, Alexandra P Steele, Brittany M Duggan, Breanne T McAlpin, Nicole G Barra, Thomas J Hawke, Jonathan P Little, Jonathan D Schertzer.

  Intermittent fasting (IF) can lower body mass during obesity, but it is unknown why certain individuals lose less fat and more lean mass during IF. We hypothesized that hyperinsulinemia and an insulin-responsive adipocyte factor regulate the balance between fat and muscle loss. Chronic elevation of insulin led to higher adipose tissue mass, larger adipocytes, and lower muscle mass after 10 weeks of 5:2 IF in obese male mice. Chronic hyperinsulinemia lowered adipose tissue interferon regulatory factor 4 (IRF4). Whole-body or adipocyte-specific deletion of Irf4 resulted in higher adipose tissue mass and lower muscle mass after IF in obese male mice in two separate models of equal or reduced caloric intake during IF. Males living with obesity and higher blood insulin levels lost more lean mass after a 48-h fast. Therefore, hyperinsulinemia and lower adipocyte IRF4 alter nutrient partitioning to promote higher adipose retention and lower muscle preservation during IF during obesity.

Keywords:  CP: metabolism; IRF4; adipose; insulin; intermittent fasting; muscle; obesity

DOI:  https://doi.org/10.1016/j.celrep.2026.117023
Cell Metab. 2026 Feb 17. pii: S1550-4131(26)00012-4. [Epub ahead of print]

Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.

Iñigo Chivite, Erika Monelli, Margalida Munar-Gelabert, Alicia G Gómez-Valadés, Abdiel Alvarado-Diaz, Macarena Pozo, Luis Varela, Sara Ramírez, Roberta Haddad-Tóvolli, Miriam Toledo, Júlia Fos-Domènech, Francisco Díaz-Castro, Iasim Tahiri, Pau García-Ramón, Mariana Ferreira, Chloé van Gelder, Anne Abot, Óscar Osorio-Conles, José Antonio Valer, Arnaud Obri, Maria Milà-Guasch, Jorge Alvarez Luis, Pilar Villacampa, Elena Eyre, Jordi Altirriba, Sabrina Genßler, Markus Haake, Christine Schuberth-Wagner, Xavier Remesar, Antonio Zorzano, Pablo M Garcia-Rovés, Francesc Ventura, Josep Vidal, Claude Knauf, Rubén Nogueiras, Tamas L Horvath, Katrien De Bock, Mariona Graupera, Marc Claret.

  Endothelial cells (ECs) are key metabolic gatekeepers, yet their role in metabolic health remains unclear. Given their central involvement in energy metabolism, mitochondria are ideally positioned to enable ECs to adapt to ever-changing metabolic requirements. Here, we explore the hypothesis that mitochondrial dynamics proteins in ECs influence whole-body metabolic status. Genetic deficiency of Mfn2 in ECs (Mfn2iΔEC), but not of Mfn1iΔEC, induces a mitohormetic response in the adipose vasculature, enhancing antioxidant defenses, mitochondrial fitness, and lipid oxidation, ultimately improving metabolic outcomes. Cultured ECs secrete the mitokine growth differentiation factor 15 (GDF15) via a forkhead box O1 (FOXO1)-dependent axis, a response also observed under stress conditions in vivo. Notably, Mfn2iΔEC mice exhibited elevated endothelial and circulating GDF15 levels, and neutralization of GDF15 partly attenuated their metabolic benefits. Consistent with mitohormetic activation, Mfn2iΔEC mice showed protection against diet-induced obesity and delayed age-related decline. Hence, vascular mitohormetic adaptations emerge as a novel mechanism promoting systemic metabolic health.

Keywords:  GDF15; aging; diabetes; endothelial cells; mitochondria; mitofusin; mitohormesis; obesity

DOI:  https://doi.org/10.1016/j.cmet.2026.01.012
Signal Transduct Target Ther. 2026 Feb 19. 11(1): 64

Hyperglutaminolysis drives senescence and aging through arginine-mTORC1 axis activation.

Honghan Chen, Ning Huang, Weitong Xu, Yu Yang, Fangfang Wang, Hui Gong, Jiao Zhou, Haoran Tai, Tingting Zhao, Jian Zhang, Ying Li, Ge Liang, Minghai Tang, Jie Li, Ming Yang, Jin Liu, Xiaoli Huang, Hengyi Xiao.

The catabolism of glutamine is essential for living organisms, so that its first step, driven by glutaminase 1 (GLS1), generally referred to as glutaminolysis, plays important roles in physiological metabolism. However, the status and impact of glutaminolysis in pathological contexts such as aging and age-related diseases remain elusive. In this study, through metabolomics analysis and different aging models, we verified the hyperactivation status of glutaminolysis in senescent cells and aged Drosophila and mice, which we term "hyperglutaminolysis". We further confirmed the aging-promoting role of this hyperglutaminolysis by addition and removal intervention experiments. Intriguingly, a novel signaling axis connecting to senescence-associated persistent mTORC1 activation was found. This pathway begins with glutaminase-catalyzed production of ammonium and glutamate, which drives arginine biosynthesis and is subsequently sensed by CASTOR1, leading to persistent mTORC1 activation. The regulatory roles of two key enzymes within this cascade, GLS1 and argininosuccinate lyase (ASL), were specifically investigated and verified by cellular and in vivo experiments, including those using stress-promoted and naturally aged animals, combined with GLS1 and ASL knockdown, and multiple rounds of metabolite analysis. In conclusion, our work positions dysregulated glutaminolysis as a key driver of aging and delineates a previously unrecognized molecular cascade that directly links glutaminolysis, arginine biosynthesis, and mTORC1 activation. These findings significantly expand our understanding of the relationship between glutamine catabolism and aging and are valuable for identifying novel intervention targets aimed at mitigating aging-related processes.

DOI: https://doi.org/10.1038/s41392-026-02576-w
Nat Commun. 2026 Feb 18.

Structural insight into hierarchical DNMT3A autoinhibition and its dysregulation in disease.

Jiuwei Lu, Emily Vig, Jianbin Chen, Kristjan H Gretarsson, Nelli Khudaverdyan, Zengyu Shao, Chao Lu, Chia-En A Chang, Jikui Song.

DNA methyltransferase DNMT3A-mediated DNA methylation is important for genomic imprinting and transcriptional regulation. However, how the regulatory domains of DNMT3A cooperate with its methyltransferase domain and histone marks to orchestrate genomic methylation remains unclear. Here we report the cryo-EM structure of DNMT3A2 with regulatory factor DNMT3L, revealing an intricate domain interaction underlying multilayered autoinhibition. The PWWP domain interacts with the ADD and methyltransferase domains to block the target recognition domain and the H3K36me2-binding pocket, thereby coupling the H3K36me2 binding with DNMT3A activation, adding a layer of allosteric regulation distinct from the previously characterized ADD-H3K4me0 regulation. Molecular dynamics simulations of the DNMT3A-DNMT3L complex further reveals that relief of DNMT3A autoinhibition involves disengagement of the CpG-recognition loop of the target recognition domain from autoinhibitory interaction, leading to enhanced accessibility of the target recognition domain loop for DNA binding and DNMT3A activation. Importantly, our combined structural, biochemical and genomic methylation analysis demonstrates that disrupting the PWWP-ADD interaction by disease-associated DNMT3A mutations leads to impaired DNMT3A autoinhibition and substrate specificity, providing a potential explanation to aberrant DNA methylation in disease.

DOI: https://doi.org/10.1038/s41467-026-69563-1
Nat Aging. 2026 Feb 19.

Visceral adiposity, metabolic health and aging.

Laurence T Maeyens, James F Nelson, Shangang Zhao.

Visceral adipose tissue (VAT) is increasingly recognized as a metabolically active organ that contributes to systemic metabolic dysfunction and aging. Accumulation of VAT is thought not merely to be a biomarker of but also a causal contributor to impaired metabolic health and reduced lifespan. In this Review, we summarize evidence from both animal and human studies to evaluate whether this causal relationship truly holds. Our assessment indicates that VAT is not inherently harmful; rather, its pathogenicity is context dependent and emerges under specific conditions, including lipid spillover combined with impaired preadipocyte differentiation, chronic inflammation, genetic susceptibility, hormonal changes and aging. We further explore how VAT-derived cytokines, exosomes, adipokines and lipotoxic metabolites mechanistically mediate its harmful effects. Lastly, we outline both established and emerging strategies aimed at reducing VAT burden or neutralizing its pathological impact. These insights highlight the view of VAT as a modifiable and context-sensitive contributor to metabolic disease and aging, and a promising target for promoting metabolic health and longevity.

DOI: https://doi.org/10.1038/s43587-026-01076-4