bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–10–12
eleven papers selected by
Xiong Weng, University of Edinburgh
  1. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
  2. Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
  3. Early-life ketone body signalling promotes beige fat biogenesis through changes in histone acetylome and β-hydroxybutyrylome.
  4. Translating cellular senescence research into clinical practice for metabolic disease.
  5. Mechanism of weight regain - The role of epigenetic modification in adipocytes.
  6. Novel UCP1-independent thermogenic mechanism identified.
  7. Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing.
  8. A ternary-code DNA methylome atlas of mouse tissues.
  9. Longevity steps on the cGAS.
  10. Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
  11. Hotspots of human mutation point to clonal expansions in spermatogonia.
  1. Sci Adv. 2025 Oct 10. 11(41): eadw4153
    TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and Parkin-independent mitophagy.
    Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Biaoxin Chai, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.
      Innate immune signaling is activated in immunometabolic diseases, including type 2 diabetes, yet its impact on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for pancreatic β cell function at baseline, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and mitophagy following metabolic stress in mouse and human islets. TRAF6 was critical for the recruitment and function of the ubiquitin-mediated (Parkin-dependent) mitophagy machinery. Glucose intolerance induced by TRAF6 deficiency following metabolic stress was reversed by concomitant Parkin deficiency by relieving obstructions in receptor-mediated (Parkin-independent) mitophagy. Our results establish that TRAF6 is vital for traffic through Parkin-mediated mitophagy and implicates TRAF6 in the cross-regulation of ubiquitin- and receptor-mediated mitophagy. Together, we illustrate that β cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
    DOI:  https://doi.org/10.1126/sciadv.adw4153
  2. Nat Commun. 2025 Oct 10. 16(1): 9022
    Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
    Fan Yu, Jingsi Duan, Zhengyin Lou, Guo-Ping Shi, Fuzhe Gong, Lingfeng Zhong, Derong Chen, Li Xu, Tingting Hong, Xinyang Hu, Jinghai Chen, Jian'an Wang, Deling Yin.
      Myocardial energy metabolism disorders are essential pathophysiology in sepsis-associated myocardial injury. Yet, the underlying mechanisms involving impaired mitochondrial respiratory function upon myocardial injury remain poorly understood. Here we identify an unannotated and cardiomyocyte-enriched long non-coding RNA, Cpat (cardiac-protector-associated transcript), that plays an important role in regulating the dynamics of cardiomyocyte mitochondrial tricarboxylic acid (TCA) cycle. Cpat is essential to the mitochondrial respiratory function by targeting key metabolic enzymes and modulating TCA cycle flux. Specifically, Cpat enhances the association of TCA cycle core components malate dehydrogenase (MDH2), citrate synthase (CS), and aconitase (ACO2). Acetyltransferase general control non-repressed protein-5 (GCN5) acetylates CS and destabilizes the MDH2-CS-ACO2 complex formation. Cpat inhibits this GCN5 activity and facilitates MDH2-CS-ACO2 complex formation and TCA cycle flux. We reveal that Cpat-mediated mitochondrial metabolic homeostasis is vital in mitigating myocardial injury in sepsis-induced cardiomyopathy, positioning Cpat as a promising therapeutic target for preserving myocardial cellular metabolism and function.
    DOI:  https://doi.org/10.1038/s41467-025-64072-z
  3. Nat Metab. 2025 Oct 09.
    Early-life ketone body signalling promotes beige fat biogenesis through changes in histone acetylome and β-hydroxybutyrylome.
    Chung-Lin Jiang, Pei-Hsiang Lai, Po-Cheng Yang, Chia-Jung Lien, Hsueh-Ping Catherine Chu, Jian-Da Lin, Sung-Jan Lin, I-Shing Yu, Fu-Jung Lin.
      Infants undergo distinct ketogenesis during the preweaning period, yet its physiological implications remain unclear. Here, we show that preweaning ketosis promotes beige fat biogenesis and improves health outcomes in adulthood. Loss of ketogenesis in neonatal mice by early weaning or ablation of Hmgcs2 hinders beige adipogenesis, subsequently exacerbating metabolic dysregulation in high-fat diet-induced obesity. Enhanced ketogenesis during lactation through exogenous ketone supplements enhances energy expenditure, beige fat formation, and mitochondrial biogenesis and respiration. Using single-cell RNA sequencing, we identified a subset of β-hydroxybutyrate-responsive adipocyte progenitor cells (APCs) expressing Cd81 that showed high beige adipogenic potential. Enhanced ketogenesis promotes the recruitment of beige APCs and their differentiation into beige adipocytes. Mechanistically, ketogenesis-derived βHB induces a switch in the histone acetylome and β-hydroxybutyrylome for transcriptional activation of beige fat biogenesis genes. Notably, enhanced ketogenesis during lactation alleviates adverse metabolic effects predisposed by parental obesity. Our study highlights that targeting preweaning ketosis to drive beige adipogenesis may offer a therapeutic approach to combat obesity and metabolic diseases in adulthood.
    DOI:  https://doi.org/10.1038/s42255-025-01378-8
  4. Nat Rev Endocrinol. 2025 Oct 06.
    Translating cellular senescence research into clinical practice for metabolic disease.
    Selim Chaib, Allyson K Palmer, Saranya P Wyles, Nicolas Musi, James L Kirkland, Tamara Tchkonia.
      Translational research on cellular senescence has led to numerous early-phase clinical trials targeting senescent cells to treat, prevent or alleviate multiple disorders and diseases, including metabolic diseases and their comorbidities. Cellular senescence is a cell fate that occurs in response to stressors, including metabolic disruptions, and is one of the hallmarks (or pillars) of ageing. In their senescent state, cells cease proliferation and can develop a senescence-associated secretory and metabolic phenotype that contributes to the pathogenesis of metabolic dysfunction associated with obesity and ageing. Metabolic stress, which is central to the development of metabolic diseases, can trigger cellular senescence, thereby enabling a vicious cycle that exacerbates metabolic dysfunction. Therapies targeting senescent cells (senotherapeutics), either alone or in combination with other gerotherapies or lifestyle interventions, hold great promise for addressing the ongoing obesity epidemic and the need for improved therapies to prevent and treat metabolic diseases and their complications and comorbidities. In this Review, we discuss novel senotherapeutics, including challenges related to the translation of these therapies and the need to establish gerodiagnostic biomarkers to track the elimination of senescent cells, define eligibility and measure efficacy, as well as considerations for clinical trial design and execution.
    DOI:  https://doi.org/10.1038/s41574-025-01187-9
  5. Acta Pharm Sin B. 2025 Sep;15(9): 4961-4963
    Mechanism of weight regain - The role of epigenetic modification in adipocytes.
    Yue Zhao, Xiwen Ma, Jianping Ye.
      
    Keywords:  Adipose tissue; Epigenetic modification; Obesity; Weight loss; Weight regain
    DOI:  https://doi.org/10.1016/j.apsb.2025.02.002
  6. Nat Rev Endocrinol. 2025 Oct 07.
    Novel UCP1-independent thermogenic mechanism identified.
    Olivia Tysoe.
      
    DOI:  https://doi.org/10.1038/s41574-025-01193-x
  7. Nat Commun. 2025 Oct 06. 16(1): 8873
    Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing.
    Thashma Ganapathy, Juntao Yuan, Melody Yuen-Man Ho, Kelvin Ka-Lok Wu, Md Moinul Hoque, Baomin Wang, Xiaomu Li, Kai Wang, Martin Wabitsch, Xuejia Feng, Yongxia Niu, Kekao Long, Qizhou Lian, Yuyan Zhu, Kenneth King-Yip Cheng.
      Trimethylamine N-oxide (TMAO) contributes to cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) recognized as its primary source. Here we demonstrate that elevated adipocyte FMO3 and its derived TMAO trigger white adipose tissue (WAT) dysfunction and its related metabolic disorders in ageing. In adipocytes, ageing or p53 activation upregulates FMO3 and TMAO levels. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism and energy and lipid homeostasis in ageing and obese mice. These improvements are associated with reduced senescence, fibrosis and inflammation in WAT. Proteomics analysis identified TMAO-interacting proteins involved in inflammasome activation in adipocytes and macrophages. Mechanistically, TMAO binds to the central inflammasome adaptor protein ASC, promoting caspase-1 activation and interleukin-1β production. Our findings uncover a pivotal role for adipocyte FMO3 in modulating TMAO production and WAT dysfunction by promoting inflammasome activation in ageing via an autocrine and paracrine manner.
    DOI:  https://doi.org/10.1038/s41467-025-63905-1
  8. Genome Biol. 2025 Oct 07. 26(1): 343
    A ternary-code DNA methylome atlas of mouse tissues.
    Sol Moe Lee, David C Goldberg, Cameron Cloud, Jared B Parker, Christopher Krapp, Christian E Loo, Elliot Kim, Ivan Zhao, Chengcheng Jin, Rishi Porecha, Marisa S Bartolomei, Rahul M Kohli, Wanding Zhou.
       BACKGROUND: DNA cytosine modifications, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), are key epigenetic regulators with distinct functions. Dissecting the ternary code (C, 5mC, 5hmC) across tissues and cell types remains a critical priority due to the limitations of traditional profiling methods based on bisulfite conversion.
    RESULTS: Here, we leverage the combined bisulfite and enzymatic (bACE) conversion with the Mouse Methylation BeadChip to generate 265 base-resolution ternary-code modification maps of 5mC and 5hmC across 29 mouse tissue types spanning 8-76 weeks of age and both sexes. Our atlas reveals a complex grammar of 5hmC distribution, jointly shaped by cell mitotic activity, chromatin states, and interplay with 5mC at the same and neighboring CpG sites. Of note, we demonstrate that 5hmC significantly complements 5mC-based biomarkers in delineating cell identity in both brain and non-brain tissues. Each modification state, including 5hmC alone, accurately discriminates tissue types, enabling high-precision machine learning classification of epigenetic identity. Furthermore, the ternary methylome variations extensively implicate gene transcriptional variation, with age-related changes correlated with gene expression in a tissue-dependent manner.
    CONCLUSIONS: Our work reveals how tissue, sex, and age jointly govern the dynamics of the two cytosine modifications, augments the scope of DNA modification biomarker discovery, and provides a reference atlas to explore epigenetic dynamics in development and disease.
    Keywords:  Aging; Cell identity; DNA methylation; Epigenetics; Hydroxymethylation; Mouse; Transcription regulation
    DOI:  https://doi.org/10.1186/s13059-025-03808-y
  9. Science. 2025 Oct 09. 390(6769): 126-127
    Longevity steps on the cGAS.
    John C Martinez, Andrei Seluanov, Vera Gorbunova.
      A DNA repair function in a cytosolic sensor demonstrates a potential role in naked mole-rat longevity.
    DOI:  https://doi.org/10.1126/science.aeb6125
  10. Science. 2025 Oct 09. 390(6769): 156-163
    Ubiquitin-mediated mitophagy regulates the inheritance of mitochondrial DNA mutations.
    Michele Frison, Brandon S Lockey, Yu Nie, Zoe Golder, Eleni Theiaspra, Cameron D Ryall, Camilla Lyons, Stephen P Burr, Malwina Prater, Lyuba V Bozhilova, Angelos Glynos, James B Stewart, Nick S Jones, Marcos R Chiaratti, Patrick F Chinnery.
      Mitochondrial synthesis of adenosine triphosphate is essential for eukaryotic life but is dependent on the cooperation of two genomes: nuclear and mitochondrial DNA (mtDNA). mtDNA mutates ~15 times as fast as the nuclear genome, challenging this symbiotic relationship. Mechanisms must have evolved to moderate the impact of mtDNA mutagenesis but are poorly understood. Here, we observed purifying selection of a mouse mtDNA mutation modulated by Ubiquitin-specific peptidase 30 (Usp30) during the maternal-zygotic transition. In vitro, Usp30 inhibition recapitulated these findings by increasing ubiquitin-mediated mitochondrial autophagy (mitophagy). We also found that high mutant burden, or heteroplasmy, impairs the ubiquitin-proteasome system, explaining how mutations can evade quality control to cause disease. Inhibiting USP30 unleashes latent mitophagy, reducing mutant mtDNA in high-heteroplasmy cells. These findings suggest a potential strategy to prevent mitochondrial disorders.
    DOI:  https://doi.org/10.1126/science.adr5438
  11. Nature. 2025 Oct 08.
    Hotspots of human mutation point to clonal expansions in spermatogonia.
    Vladimir Seplyarskiy, Mikhail A Moldovan, Evan Koch, Prathitha Kar, Matthew D C Neville, Raheleh Rahbari, Shamil Sunyaev.
      In renewing tissues, mutations conferring selective advantage may result in clonal expansions1-4. In contrast to somatic tissues, mutations driving clonal expansions in spermatogonia (CES) are also transmitted to the next generation. This results in an effective increase of de novo mutation rate for CES drivers5-8. CES was originally discovered through extreme recurrence of de novo mutations causing Apert syndrome5. Here, we develop a systematic approach to discover CES drivers as hotspots of human de novo mutation. Our analysis of 54,715 trios ascertained for rare conditions9-13, 6,065 control trios12,14-19 and population variation from 807,162 mostly healthy individuals20 identifies genes manifesting rates of de novo mutations inconsistent with plausible models of disease ascertainment. We propose 23 genes hypermutable at loss-of-function (LoF) sites as candidate CES drivers. An extra 17 genes feature hypermutable missense mutations at individual positions, suggesting CES acting through gain of function. CES increases the average mutation rate roughly 17-fold for LoF genes in both control trios and sperm and roughly 500-fold for pooled gain-of-function sites in sperm21. Positive selection in the male germline elevates the prevalence of genetic disorders and increases polymorphism levels, masking the effect of negative selection in human populations. Despite the excess of mutations in disease cohorts for 19 LoF CES driver candidates, only 9 show clear evidence of disease causality22, suggesting that CES may lead to false-positive disease associations.
    DOI:  https://doi.org/10.1038/s41586-025-09579-7
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