bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–01–25
six papers selected by
Xiong Weng, University of Edinburgh
  1. Mitochondrial retrograde signal through GCN5L1 transition-mediated PPARγ stabilization promotes MASLD development.
  2. NCOA1 is a gatekeeper of the sexually dimorphic thermogenic activity of white adipose tissue.
  3. PRC2-Related Epigenetic Age Acceleration in Acute Myeloid Leukemia with DNMT3A and IDH2 Mutations.
  4. G9a-mediated H3K9me2 orchestrates intestinal epithelial regeneration through epigenetic silencing of cell cycle-related genes.
  5. TRIM40 Drives Pathological Cardiac Hypertrophy and Heart Failure via Ubiquitination of PKN2.
  6. Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance.
  1. JCI Insight. 2026 Jan 23. pii: e196695. [Epub ahead of print]11(2):
    Mitochondrial retrograde signal through GCN5L1 transition-mediated PPARγ stabilization promotes MASLD development.
    Jiaqi Zhang, Danni Wang, Qiqi Tang, Yaoshu Yue, Xin Lu, Xiuya Hu, Yitong Han, Jiarun Chen, Zihan Wang, Xue Bai, Kai Zhang, Yongsheng Chang, Longhao Sun, Lu Zhu, Lingdi Wang.
      Mitochondrial retrograde signaling plays crucial roles in maintaining metabolic homeostasis via regulating genome modification and oxidative responsive gene expression. In this study, we identified GCN5L1, a protein localized in both mitochondria and cytoplasm, and demonstrated its specific translocation from mitochondria to cytoplasm during lipid overload and high-fat diet feeding. Using transcriptome and proteome analyses, we identified that cytoplasmic GCN5L1 binds to and promotes the acetylation of PPARγ at lysine 289 (K289). This acetylation protected PPARγ from ubiquitination-mediated degradation by proteasome. GCN5L1 translocation enhanced protein stability of PPARγ and subsequently promoted lipid accumulation in both cultured cells and murine models. Our study further reveals that PPARγ-K289 mutation reduces the ubiquitination of PPARγ and exacerbates liver steatosis in mice. These findings unveil a mitochondrial retrograde signaling during lipid overload, which regulates the crucial lipogenic transcriptional factor. This discovery elucidates an unrecognized mitochondrial function and mechanism underlying hepatic lipid synthesis.
    Keywords:  Cell biology; Hepatology; Mitochondria; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.196695
  2. Nat Commun. 2026 Jan 20. 17(1): 717
    NCOA1 is a gatekeeper of the sexually dimorphic thermogenic activity of white adipose tissue.
    Mounia Tannour-Louet, Didier F Pisani, Hichem Bouguerra, Alycia Zedda, Marine Bourcier, Noura Lamghari, Nadine Gautier, Benoit Chaput, Elodie Riant, Anne Bouloumié, Emilie Montastier, Nathalie Viguerie, Dominique Langin, Ez-Zoubir Amri, Pierre Gourdy, Jean-François Tanti, Mireille Cormont, Jean-François Louet.
      Premenopausal women preferentially store fat in subcutaneous depots, which provides protection against cardiometabolic disease. Their white adipose tissue also exhibits a more thermogenic, brown-like profile compared with that of men, yet the mechanisms underlying this sex-specific benefit remain unclear. Here, we show that Nuclear Receptor Coactivator 1 is highly expressed in human subcutaneous fat, with further induction during the conversion of white to beige adipocytes and in response to caloric restriction. Loss of Nuclear Receptor Coactivator 1 in subcutaneous adipocytes revealed a cell-autonomous role in promoting beiging by directly regulating the thermogenic factor Uncoupling Protein 1 and sex-dependent mitochondrial gene networks activated by cold and adrenergic stimulation. Acting together with GATA binding protein 3, it establishes elevated basal thermogenic tone in female subcutaneous fat. Female mice lacking this coregulator progressively developed obesity and glucose intolerance, and a male-like fat distribution, with increased visceral fat and reduced beige adipocytes. These findings identify Nuclear Receptor Coactivator 1 as a sex-specific determinant of adipose tissue remodelling and female metabolic resilience.
    DOI:  https://doi.org/10.1038/s41467-025-65229-6
  3. Adv Biol (Weinh). 2026 Jan;10(1): e00710
    PRC2-Related Epigenetic Age Acceleration in Acute Myeloid Leukemia with DNMT3A and IDH2 Mutations.
    Zhengyi Yan, Luowei Yuan, Jinxing Wang, Shen Gu, Yong Lei.
      Aging is closely linked to epigenetic remodeling, with DNA methylation (DNAm) emerging as a robust biomarker for estimating epigenetic age (EA) and quantifying senescence. Dysregulation of aging-associated DNAm has been implicated in diverse pathologies, including acute myeloid leukemia (AML). However, the effect of these epigenetic alterations in diseases and the underlying mechanism remains largely uncharacterized. Using causality-enriched epigenetic clocks, we identified that adaptive DNAm dynamics are sensitive to short-term therapeutic intervention in treating AML and may exhibit adaptive effects linked to better health outcomes. Subsequently, integrative genomic analysis showed significant associations between epigenetic aging and recurrent AML driver mutated genes, particularly DNMT3A and IDH2. The elevated adaptive aging associates with improved overall survival in cytogenetically normal AML harboring these mutations, highlighting its prognostic value in specific genomic contexts. Mechanistic analysis demonstrated that differentially methylated CpG sites in mutated gene-specific AML subtypes are enriched at polycomb repressive complex 2 (PRC2) targets. These findings link mutation-specific epigenetic aging, PRC2-mediated methylation dynamics, and AML pathogenesis, offering insights into how aging-related epigenetic dysregulation fosters malignant transformation. This study shows that AdaptAge can help reveal AML‑related DNAm dynamics when combined with genetic stratification, suggesting a path toward future biomarker development.
    Keywords:  DNA methylation; acute myeloid leukemia; epigenetic aging; polycomb repressive complex 2
    DOI:  https://doi.org/10.1002/adbi.202500710
  4. Nat Commun. 2026 Jan 19.
    G9a-mediated H3K9me2 orchestrates intestinal epithelial regeneration through epigenetic silencing of cell cycle-related genes.
    Jingzhou Chen, Xiaoliang Shi, Xinyi Zhou, Ju Huang, Linghao Xia, Zhen Hu, Jiaji Gu, Xiaole Sheng, Xiaolong Ge, Xudong Fu, Qian Xiao, Wei Zhou, Rongpan Bai, Zhengping Xu, Jinghao Sheng.
      Histone modifications play an important role in intestinal homeostasis and regeneration. Here, we identify histone H3 lysine 9 di-methylation (H3K9me2) as an epigenetic regulator of intestinal epithelial repair through mass spectrometry-based screening of histone modifications. We then find that H3K9me2 and its methyltransferase G9a levels are reduced during acute injury and progressively increase during regeneration in both mouse models and human clinical samples. Genetic ablation of G9a in intestinal epithelial cells or pharmacological inhibition of its enzymatic activity substantially impairs intestinal regeneration and reduces survival following irradiation. Mechanistically, integrative genomic analyses reveal that G9a-mediated H3K9me2 suppresses chromatin accessibility and transcriptional activity of cell cycle arrest genes, including Rb1cc1, Rb1, Cdkn1a, and Pten, thereby promoting intestinal stem cell proliferation. Furthermore, we elucidate that IL-4-STAT6 signaling controls G9a expression during regeneration, i.e., IL-4 upregulation leads to STAT6 phosphorylation and subsequent transcriptional activation of G9a. These findings establish the IL-4-STAT6-G9a-H3K9me2 regulatory axis as a critical epigenetic mechanism controlling intestinal regeneration with therapeutic potential for gastrointestinal disorders.
    DOI:  https://doi.org/10.1038/s41467-026-68626-7
  5. Adv Sci (Weinh). 2026 Jan 22. e21337
    TRIM40 Drives Pathological Cardiac Hypertrophy and Heart Failure via Ubiquitination of PKN2.
    Risheng Zhao, Xiaoli Cui, Huizhu Du, Zhuoqun Wang, Chang Liu, Linxin Zhang, Jianing Qi, Di Yang, Hui Yu, Shuang Yan, Wei Liu, Haiming Sun, Mengyang Wang.
      Pathological cardiac hypertrophy is a major predisposing factor for heart failure (HF). This study investigates the role of the E3 ubiquitin ligase Tripartite Motif-Containing 40 (TRIM40) in cardiac hypertrophy. Using TRIM40 knockout (TRIM40-/-), cardiac-specific knockdown and overexpressing mice, pathological hypertrophy was induced by angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Results showed that TRIM40 expression was upregulated in hypertrophic hearts. TRIM40 deficiency attenuated cardiac hypertrophy and dysfunction, whereas its overexpression exacerbated pathological remodeling. Mechanistically, TRIM40 binds PKN2 via its B-box domain and, in a manner requiring its C29-dependent E3 ligase activity, promotes K63-linked ubiquitination of PKN2. This leads to enhanced PKN2 phosphorylation at Ser815 and activation of downstream signaling. Pharmacological inhibition of PKN2 attenuated cardiac remodeling induced by TRIM40 overexpression. These findings reveal that TRIM40 drives cardiac hypertrophy through K63-linked ubiquitination and activation of PKN2, identifying TRIM40 as a promising candidate for therapeutic intervention in HF.
    Keywords:  PKN2; TRIM40; angiotensin II; cardiac hypertrophy; heart failure; transverse aortic constriction
    DOI:  https://doi.org/10.1002/advs.202521337
  6. Nat Metab. 2026 Jan 20.
    Distinct sympathetic projections to brown fat regulate thermogenesis and glucose tolerance.
    Daniele Neri, Seoeun Lee, Alexis M Fohn, Xinhong Chen, Dominique Bozec, Alexandre J Lafond, Natalie R Lopatinsky, Lucas Castro E Souza, Gawri Mohanan Nair, Angela M Ramos-Lobo, Markus Heine, Anna Worthmann, Joerg Heeren, Vidhu V Thaker, Viviana Gradinaru, Lori M Zeltser.
      Brown adipose tissue (BAT) contributes to thermoregulation and glucose metabolism, but how these functions are coordinated remains unclear. While thermogenesis in the activated BAT typically coincides with increased blood flow and glucose uptake1-5, several pathophysiological and nutritional states dissociate these processes6,7, suggesting they are governed by distinct sympathetic circuits. Here we identify subpopulations of sympathetic neurons in the stellate ganglion that mediate distinct functions of intrascapular BAT (iBAT) in mice. Two main types of sympathetic neurons project to iBAT: those that innervate the organ parenchyma and those that innervate the large blood vessels feeding the depot8-12. Here we develop a toolkit to parse the functions of these neuronal subclasses through targeted chemogenetic activation of projections to iBAT, while sparing other organs, and single-cell transcriptomics coupled to retrograde tracing from iBAT to the stellate ganglion. We find that stimulation of the parenchymal projections increases blood flow and thermogenesis in iBAT, without affecting circulating glucose levels. Conversely, stimulation of the vascular projections improves glucose tolerance but does not alter blood flow or thermogenesis in iBAT. These data provide a mechanistic explanation for the dissociation between the thermogenic and glycaemic effects of BAT activation13-16.
    DOI:  https://doi.org/10.1038/s42255-025-01429-0
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