bims-obesme 2026-04-05 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2026–04–05
nine papers selected by
Xiong Weng, University of Edinburgh

Irisin ameliorates obesity and insulin resistance via adipose tissue IL-33 and regulatory T cells.
Inhibition of adipocyte RUNX1/2 enhances adipose tissue thermogenesis through distinct mechanisms.
Homoharringtonine exhibits senotherapeutic activity that mitigates diet- and age-associated obesity and insulin resistance and extends lifespan in mice.
Ca 2+ influx through ER-plasma membrane contacts is required for brown fat thermogenesis and metabolic health.
Maltol induces diabetic fragility fractures by disrupting the balance of bone remodeling.
The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.
Advancing precision health discovery in a genetically diverse health system.
Pharmacological administration of FGF21 reverses obesity through a parabrachial-projecting neuron population in the hindbrain.
The 1000 Chinese Pangenome empowers medical and population genetics.

Nat Metab. 2026 Apr 03.

Irisin ameliorates obesity and insulin resistance via adipose tissue IL-33 and regulatory T cells.

Mu A, Gang Wang, Nathan W Zammit, Laura Roth, Yasheng Maierhaba, Dina Bogoslavski, Chufan Cai, P Kent Langston, Qiuyang Zhang, Inna S Afonina, Rudi Beyaert, Bruce M Spiegelman, Diane Mathis.

Irisin is an exercise-induced myokine that confers multiple physiological benefits, including browning of subcutaneous adipose tissue in mice. However, the underlying cellular and molecular mechanisms of irisin's effects on obesity are unclear. Here, we show that irisin modulates adipose tissue inflammation by increasing interleukin (IL)-33 production and preserving ST2+ regulatory T cells in white adipose tissues. Administered chronically to high-fat-diet-fed male mice, irisin preserves visceral adipose tissue (VAT) levels of ST2+ regulatory T cells, an important immunomodulatory population that usually contracts after long-term high-fat-diet feeding. This protection results from increases in IL-33-producing mesenchymal stromal cells and IL-33 levels in VAT. These effects are primary, as irisin directly induces IL-33 expression in cultured VAT mesenchymal stromal cells. Irisin-mediated changes in VAT IL-33 dynamics are accompanied by IL-33-dependent upregulation of thermogenic gene expression in subcutaneous adipose tissue. These irisin-driven cell-cell and inter-tissue interactions improve obesity and glucose intolerance, and increase energy expenditure, with no reduced food intake and muscle loss in obese mice.

DOI: https://doi.org/10.1038/s42255-026-01491-2
Nat Commun. 2026 Apr 02.

Inhibition of adipocyte RUNX1/2 enhances adipose tissue thermogenesis through distinct mechanisms.

Cuihua Wang, Na He, Shixiang Wang, Miao Lei, Jie Yao, Li Lin, Xue Ding, Jiaman Lin, Yixin Chen, Qiaoyun Long, Hannah Xiaoyan Hui, Liwei Xie, Yun-Shen Chan, Nan Cao, Shanshan Gu, Wenxiang Hu.

Thermogenic adipocytes hold significant therapeutic promise for combating obesity and metabolic diseases due to their capacity to dissipate energy as heat. However, the transcriptional regulatory mechanisms underlying thermogenic adipocyte activation remain incompletely understood. Here, we identified RUNX1 and RUNX2 as key transcriptional barriers to thermogenic adipocyte differentiation and activation. RUNX1/2 expression is dynamically suppressed by thermal stress and positively associated with adverse metabolic traits. Genetic deletion of RUNX1 or RUNX2 in adipocytes enhances beige fat formation but differentially influences systemic metabolism in male mice. Conversely, enforced RUNX1/2 expression suppresses thermogenic gene programs and blunts thermogenic adipocyte activation. Mechanistically, RUNX1 recruits HDAC1 to enforce epigenetic silencing of thermogenic loci, whereas RUNX2 governs thermogenic cell fate through phase-separation-dependent repression. Notably, pharmacological inhibition of RUNX1/2 enhances adipose thermogenesis and improves energy metabolism. Our findings unveil an unrecognized role for RUNX in adipose thermogenesis, highlighting their potential as therapeutic targets for metabolic disease intervention.

DOI: https://doi.org/10.1038/s41467-026-71266-6
Nat Commun. 2026 Mar 31. pii: 2700. [Epub ahead of print]17(1):

Homoharringtonine exhibits senotherapeutic activity that mitigates diet- and age-associated obesity and insulin resistance and extends lifespan in mice.

Eok-Cheon Kim, Han-Byul Jung, Yu-Kyoung Park, Youlim Son, Hye-Na Cha, Yash Patel, Ju Hee Lee, Minah Choi, Soyoung Park, Il-Kug Kim, Lauren Pickel, Seungju Lee, Yuna Ha, Min-Gyeong Shin, Qiwei Zhang, Jielin Yang, Bruno Rodrigues de Oliveira, Nathaniel Vo, Annie Yew, Jacques Togo, Kafi N Ealey, Su-Ryun Jung, Sunjin Moon, Hye-Jin Yoon, Jee-Young Lee, Hoon-Ki Sung, Jae-Ryong Kim, So-Young Park.

The accumulation of senescent cells in white adipose tissue (WAT) is closely associated with the functional decline of WAT and plays a causal role in the pathogenesis of metabolic diseases. Therefore, the elimination of senescent cells in WAT holds promise for the treatment and prevention of age-related metabolic diseases. Using a drug-repositioning strategy for 2150 clinically applied compounds, we discover that homoharringtonine (HHT), an FDA-approved anti-leukemic drug, manifests senotherapeutic activity in vitro in multiple cell types including human preadipocytes, while inflicting minimal cytotoxicity to non-senescent cells. HHT treatment prevents diet- or age-induced metabolic abnormalities in male mice targeting senescent adipocytes and preadipocytes to improve WAT function and reduce WAT inflammation. Moreover, HHT treatment attenuates age-associated phenotypes of human adipose tissue. Mechanistically, the senotherapeutic effects of HHT are mediated through the direct interaction of HHT with heat shock protein family A member 5 (HSPA5). Importantly, we found that HHT treatment delays aging and extends the lifespan in progeroid and aged mice. Our study demonstrates the novel senotherapeutic potential of HHT to mitigate age- and obesity-related metabolic dysfunction and extend longevity in mice.

DOI: https://doi.org/10.1038/s41467-026-70475-3
bioRxiv. 2026 Mar 23. pii: 2026.03.20.712802. [Epub ahead of print]

Ca 2+ influx through ER-plasma membrane contacts is required for brown fat thermogenesis and metabolic health.

J Zhou, C Dogan, L L Artico, K Rodrigues, S Hakam, T Kim, V Xu, K Lapenta, M Kang, D M Jorgens, S B Widenmaier, G Parlakgul, A P Arruda.

Brown adipose tissue (BAT) exhibits exceptional metabolic plasticity, rapidly increasing energy expenditure to sustain thermogenesis during cold exposure. This high metabolic activity imposes substantial demands on cellular systems, requiring robust adaptive mechanisms to maintain homeostasis and prevent cellular stress. Yet, the pathways that support and coordinate these adaptive responses in brown adipocytes remain incompletely understood. Here, we identify a cold-induced adaptive program in BAT characterized by the formation of endoplasmic reticulum-plasma membrane (ER-PM) contact sites and the activation of store-operated calcium entry (SOCE), which is essential for maintaining brown adipocyte health during thermogenic activation. Cold exposure enhances ER-PM contacts and upregulates the expression of STIM and Orai proteins, key mediators of SOCE. Loss of STIM in brown adipocytes disrupts intracellular Ca²⁺ homeostasis and induces aberrant aggregation of ER membranes. STIM deficiency also impairs cold-induced mitochondrial fission resulting in hyperfused mitochondria with reduced oxidative capacity, independently of UCP1 abundance. Importantly, mice lacking STIM in BAT exhibit impaired lipid oxidation, are cold intolerant and develop exacerbated peripheral insulin resistance when challenged with a high-fat diet. Together, these findings identify ER-PM remodeling and STIM-mediated SOCE as a central regulator that links organelle architecture to brown adipocyte function and contributes to whole-body metabolic homeostasis.

DOI: https://doi.org/10.64898/2026.03.20.712802
Cell Metab. 2026 Mar 27. pii: S1550-4131(26)00095-1. [Epub ahead of print]

Maltol induces diabetic fragility fractures by disrupting the balance of bone remodeling.

Jinyang Wang, Ziyuan Wang, Jinyi Feng, Ying Zhang, Lizheng Yao, Yiran Zhang, Ruijie Zhang, Jingyi Cai, Hao Yu, Songhan Deng, Xinrui Chen, Rui Liang, Caoxin Huang, Jia Li, Xuejun Li, Qinxi Li, Xiulin Shi.

  Type 2 diabetes is a major risk factor for fragility fractures, yet the contributors to skeletal fragility remain unclear. Through integrated clinical metabolomics, in vivo, and in vitro analyses, we identify maltol-a widely used food additive-as a previously unrecognized risk factor for hyperglycemia-associated bone fragility. Metabolomic profiling of femoral neck tissue from individuals with fragility fractures showed diabetes-associated maltol accumulation, and elevated circulating maltol levels correlated with increased fracture incidence. Mechanistically, maltol inhibits osteoblast differentiation via Wnt/β-catenin and promotes osteoclast maturation through nuclear factor κB (NF-κB) signaling, disrupting bone remodeling. These effects are amplified under hyperglycemia, while insulin reversal of glucose levels mitigates maltol-induced skeletal deterioration in mouse models. Given the widespread use of maltol in processed foods, these findings suggest that food additive safety should consider metabolic context and call for disease-specific dietary exposure guidelines to reduce fracture risk in diabetes.

Keywords:  bone remodeling; diabetes mellitus; fragility fractures; maltol

DOI:  https://doi.org/10.1016/j.cmet.2026.03.001
Sci Adv. 2026 Apr 03. 12(14): eaea4279

The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome.

Sarah J Shemtov, Eric McGann, Lucy Carrillo, Sangmin Lee, Herbert Anson, Eric Hwang, Claire S Chung, Jaye L Weinert, Maria-Eleni Anagnostou, Guan-Ju D Lai, Bert M Verheijen, Junxiang Wan, Ivetta Vorobyova, Monica Sanchez-Contreras, Cheryl A Conover, Max A Thorwald, Pinchas Cohen, Scott R Kennedy, Jean-François Gout, Suraiya Haroon, Marc Vermulst.

Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

DOI: https://doi.org/10.1126/sciadv.aea4279
Cell. 2026 Mar 27. pii: S0092-8674(26)00274-6. [Epub ahead of print]

Advancing precision health discovery in a genetically diverse health system.

UCLA Precision Health Data Discovery Repository Working Group

  Linking genetic data with electronic health records in hospital biobanks promises to advance precision medicine, but limited ancestral diversity constrains discovery and generalizability. We analyzed 93,936 participants from the UCLA ATLAS Community Health Initiative to inform disease prevalence and genetic risk across five continental and 36 fine-scale ancestry groups. We discovered numerous unreported gene-phenotype associations, including FN3K with intestinal disaccharidase deficiency in Europeans and admixed Americans. Polygenic scores (PGS) robustly predicted common diseases, with effects markedly diminished in non-Europeans. Furthermore, we reduced the pronounced European bias in curated clinical variants using computational predictors, uncovering unreported disease-gene associations, including ANKZF1 and peripheral vascular disease in African Americans. Longitudinal data revealed that semaglutide efficacy varies across ancestries, is associated with PGS for type 2 diabetes, and is modulated by genetic variation in PTPRU. These findings illustrate how ancestrally diverse biobanks from a single health system yield robust disease associations and pharmacogenomic insights.

Keywords:  GLP-1 receptor agonists; ancestry; electronic health records; exome-wide association study; genetic association; genomic medicine; health-system biobank; phenome-wide association study; polygenic scores; semaglutide

DOI:  https://doi.org/10.1016/j.cell.2026.03.007
Cell Rep. 2026 Mar 31. pii: S2211-1247(26)00171-3. [Epub ahead of print]45(4): 117093

Pharmacological administration of FGF21 reverses obesity through a parabrachial-projecting neuron population in the hindbrain.

Yunfan Lin, Kristin E Claflin, Iltan Aklan, Donald A Morgan, Andrew I Sullivan, Michael C Rudolph, Kamal Rahmouni, Matthew J Potthoff.

  The obesity epidemic is associated with significant healthcare and economic burdens. Pharmacological administration of the endocrine hormone fibroblast growth factor 21 (FGF21) increases energy expenditure and reverses obesity. However, the central targets and neural pathways for these metabolic benefits remain elusive. Here, we demonstrate that β-klotho (KLB)-expressing neurons in the hindbrain, specifically the nucleus of the solitary tract (NTS) and area postrema (AP), are both necessary and sufficient for FGF21's effect on energy expenditure and weight loss. These pharmacological benefits are mediated largely by NTS/AP KLB-expressing neurons that project to the parabrachial nucleus (PBN) and not the hypothalamus. Our results provide insights into the central mechanisms of pharmacological FGF21 action to modulate energy homeostasis.

Keywords:  CP: metabolism; CP: neuroscience; FGF21; area postrema; betaKlotho; body weight; brown adipose tissue; nucleus of the solitary tract

DOI:  https://doi.org/10.1016/j.celrep.2026.117093
Nature. 2026 Apr 01.

The 1000 Chinese Pangenome empowers medical and population genetics.

Yifei Wang, Zhongqu Duan, Dan Chen, Dandan Shi, Yi Ding, Zhibin Wang, Baoqing Li, Zhiyi Wang, Minmin Guo, Wen Yang, Junren Hou, Wenhao Chen, Yazhou Guo, Wenjie Wei, Yujie Cao, Xiwei Sun, Weiyang Bai, Mingdong Lu, Ting Qi, Xian Shen, Jian Yang.

Pangenomes are revolutionizing our ability to resolve genomic regions with complex variations1. However, existing human pangenomes2,3, constrained by small sample sizes, provide limited utility for medical and population genetic applications. Here we generated 1,116 diploid genome assemblies (55 de novo and 1,061 pangenome-informed) with an average size of 2.98 Gb and a mean quality value of 46 as part of the 1000 Chinese Pangenome (1KCP) project. On the basis of these assemblies, we constructed a pangenome comprising 405.3 million base pairs of sequences absent from the current references GRCh38 and CHM13, including 26.2 million base pairs of functional genic and predicted regulatory elements. We catalogued a full spectrum of genetic variation, including 35.4 million small variants, 110,530 structural variants (SVs), 485,575 tandem repeats (TRs) and 0.86 million nested variants embedded in non-reference sequences. This extensive dataset enabled detailed characterization of multiscale genic variations relevant to medical genetics, including gene-altering SVs, TR expansions, gene cluster variations and HLA gene haplotypes. Coupled with the 1KCP gene expression data, we conducted pan-variant expression quantitative trait locus (eQTL) mapping to analyse diverse variant types. We identified 3,256 eQTLs involving complex variants (SVs, TRs and nested variants) and elucidated their regulatory complexity. Finally, we developed a 1KCP pan-variant imputation reference panel, which provides multitype genetic markers to enhance the resolution of future association studies. This resource advances our understanding of complex variants and their functional implications to provide new insights into human health.

DOI: https://doi.org/10.1038/s41586-026-10315-y