bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–09–21
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. Single-nucleus mRNA-sequencing reveals dynamics of lipogenic and thermogenic adipocyte populations in murine brown adipose tissue in response to cold exposure.
  2. Peroxisomal metabolism of branched fatty acids regulates energy homeostasis.
  3. Systems Age: a single blood methylation test to quantify aging heterogeneity across 11 physiological systems.
  4. Covariation MS uncovers a protein that controls cysteine catabolism.
  5. Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome.
  6. NRF2-REGγ-ACADM/KLF15 Signaling Pathway Regulates the Browning of White Adipose Tissue to Modulate Obesity.
  7. Advancing biological understanding of cellular senescence with computational multiomics.
  8. Can muscle avert GLP1R weight plateau and regain?
  9. Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.
  10. Metabolic hallmarks of type 2 diabetes compromise T cell function.
  11. Genetic architecture of plasma metabolome in 254,825 individuals.
  12. Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.
  13. Increased levels of syndecan-3 are associated with childhood obesity.
  1. Mol Metab. 2025 Sep 11. pii: S2212-8778(25)00159-0. [Epub ahead of print] 102252
    Single-nucleus mRNA-sequencing reveals dynamics of lipogenic and thermogenic adipocyte populations in murine brown adipose tissue in response to cold exposure.
    Janina Behrens, Tongtong Wang, Christoph Kilian, Anna Worthmann, Mark A Herman, Joerg Heeren, Lorenz Adlung, Ludger Scheja.
      Brown adipose tissue (BAT) comprises a heterogeneous population of adipocytes and non-adipocyte cell types. To characterize these cellular subpopulations and their adaptation to cold, we performed single-nucleus mRNA-sequencing (snRNA-seq) on interscapular BAT from mice maintained at room temperature or exposed to acute (24h) or chronic (10 days) cold (6 °C). To investigate the role of the de novo lipogenesis (DNL)-regulating transcription factor carbohydrate response element-binding protein (ChREBP), we analyzed control and brown adipocyte-specific ChREBP knockout mice. We identified different cell populations, including seven brown adipocyte subtypes with distinct metabolic profiles. One of them highly expressed ChREBP and DNL enzymes. Notably, these lipogenic adipocytes were highly sensitive to acute cold exposure, showing a marked depletion in BAT of control mice that was compensated by other brown adipocyte subtypes maintaining DNL. Chronic cold exposure resulted in an expansion of basal brown adipocytes and adipocytes putatively derived from stromal and endothelial precursors. In ChREBP-deficient mice, lipogenic adipocytes were almost absent under all conditions, identifying the transcription factor as a key determinant of this adipocyte subtype. Detailed expression analyses revealed Ttc25 as a specific marker of lipogenic brown adipocytes and as a downstream target of ChREBP. Furthermore, pathway and cell-cell interaction analyses implicated a Wnt-ChREBP axis in the maintenance of lipogenic adipocytes, with Wnt ligands from stromal and muscle cells providing instructive cues. Our findings provide a comprehensive atlas of BAT cellular heterogeneity and reveal a critical role for ChREBP in lipogenic adipocyte identity, with implications for BAT plasticity and metabolic function.
    Keywords:  Brown adipose tissue; Carbohydrate response element-binding protein; Cold exposure; De novo lipogenesis; Energy metabolism; Single nucleus RNA-seq
    DOI:  https://doi.org/10.1016/j.molmet.2025.102252
  2. Nature. 2025 Sep 17.
    Peroxisomal metabolism of branched fatty acids regulates energy homeostasis.
    Xuejing Liu, Anyuan He, Dongliang Lu, Donghua Hu, Min Tan, Abenezer Abere, Parniyan Goodarzi, Bilal Ahmad, Brian Kleiboeker, Brian N Finck, Mohamed Zayed, Katsuhiko Funai, Jonathan R Brestoff, Ali Javaheri, Patricia Weisensee, Bettina Mittendorfer, Fong-Fu Hsu, Paul P Van Veldhoven, Babak Razani, Clay F Semenkovich, Irfan J Lodhi.
      Brown and beige adipocytes express uncoupling protein 1 (UCP1), a mitochondrial protein that dissociates respiration from ATP synthesis and promotes heat production and energy expenditure. However, UCP1-/- mice are not obese1-5, consistent with the existence of alternative mechanisms of thermogenesis6-8. Here we describe a UCP1-independent mechanism of thermogenesis involving ATP-consuming metabolism of monomethyl branched-chain fatty acids (mmBCFA) in peroxisomes. These fatty acids are synthesized by fatty acid synthase using precursors derived from catabolism of branched-chain amino acids9 and our results indicate that β-oxidation of mmBCFAs is mediated by the peroxisomal protein acyl-CoA oxidase 2 (ACOX2). Notably, cold exposure upregulated proteins involved in both biosynthesis and β-oxidation of mmBCFA in thermogenic fat. Acute thermogenic stimuli promoted translocation of fatty acid synthase to peroxisomes. Brown-adipose-tissue-specific fatty acid synthase knockout decreased cold tolerance. Adipose-specific ACOX2 knockout also impaired cold tolerance and promoted diet-induced obesity and insulin resistance. Conversely, ACOX2 overexpression in adipose tissue enhanced thermogenesis independently of UCP1 and improved metabolic homeostasis. Using a peroxisome-localized temperature sensor named Pexo-TEMP, we found that ACOX2-mediated fatty acid β-oxidation raised intracellular temperature in brown adipocytes. These results identify a previously unrecognized role for peroxisomes in adipose tissue thermogenesis characterized by an mmBCFA synthesis and catabolism cycle.
    DOI:  https://doi.org/10.1038/s41586-025-09517-7
  3. Nat Aging. 2025 Sep;5(9): 1880-1896
    Systems Age: a single blood methylation test to quantify aging heterogeneity across 11 physiological systems.
    Raghav Sehgal, Yaroslav Markov, Chenxi Qin, Margarita Meer, Courtney Hadley, Aladdin H Shadyab, Ramon Casanova, JoAnn E Manson, Parveen Bhatti, Ann Z Moore, Eileen M Crimmins, Sara Hagg, Themistocles L Assimes, Eric A Whitsel, Albert T Higgins-Chen, Morgan Levine.
      Aging occurs at different rates across individuals and physiological systems, but most epigenetic clocks provide a single age estimate, overlooking within-person variation. Here we developed systems-based DNA methylation clocks that measure aging in 11 distinct physiological systems-Heart, Lung, Kidney, Liver, Brain, Immune, Inflammatory, Blood, Musculoskeletal, Hormone and Metabolic-using data from a single blood draw. By integrating supervised and unsupervised machine learning with clinical biomarkers, functional assessments and mortality risk, we derived system-specific scores that outperformed existing global clocks in predicting relevant diseases and aging phenotypes. We also created a composite Systems Age score to capture overall multisystem aging. Clustering individuals based on these scores revealed distinct biological aging subtypes, each associated with unique patterns of health decline and disease risk. This framework enables a more granular and clinically relevant assessment of biological aging and may support personalized approaches to monitor and target system-specific aging processes.
    DOI:  https://doi.org/10.1038/s43587-025-00958-3
  4. Nature. 2025 Sep 17.
    Covariation MS uncovers a protein that controls cysteine catabolism.
    Haopeng Xiao, Martha Ordonez, Emma C Fink, Taylor A Covington, Hilina B Woldemichael, Junyi Chen, Mika Sarkin Jain, Milan H Rohatgi, Shelley M Wei, Nils Burger, Muneeb A Sharif, Julius Jan, Yaoyu Wang, Jonathan J Petrocelli, Katherine Blackmore, Amanda L Smythers, Bingsen Zhang, Matthew Gilbert, Hakyung Cheong, Sumeet A Khetarpal, Arianne Smith, Dina Bogoslavski, Yu Lei, Laura Pontano Vaites, Fiona E McAllister, Nick Van Bruggen, Katherine A Donovan, Edward L Huttlin, Evanna L Mills, Eric S Fischer, Edward T Chouchani.
      The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.
    DOI:  https://doi.org/10.1038/s41586-025-09535-5
  5. Sci Adv. 2025 Sep 19. 11(38): eadw2539
    Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome.
    Ximena Hildebrandt, Önay Veli, Armel Hyoubi, Julia Zinngrebe, Ali T Abdallah, Julian Rodefeld, Anne Hoffmann, Liane Gardeweg, Öykü Kaya, Elena Wagner, Andreas Lindhorst, Matea Poggenberg, Yuan Wang, Joëlle Dimmler, Jutta Schillings, Pegi Koci, Francesca Bonechi, Lucas Valdez Capuccino, Christine Kiefer, Konstantinos Kelepouras, Adhideb Ghosh, Falko Noé, Christian Wolfrum, Michael Singer, Gianmaria Liccardi, Tom Luedde, Aslihan Yavas, Ahmed Ghallab, Jan G Hengsler, Philipp Antczak, Martin Gericke, Holger Winkels, Matthias Blüher, Henning Walczak, Alessandro Annibaldi, Pamela Fischer-Posovszky, Nieves Peltzer.
      Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signaling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates nondegradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF receptor-1. Here, we show that mice lacking HOIP, the Lin-E3 ligase catalytic subunit of LUBAC, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a fundamental developmental role for Lin-Ub in adipocytes by mitigating cell death-driven adipose tissue inflammation and protecting against obesity-related metabolic syndrome.
    DOI:  https://doi.org/10.1126/sciadv.adw2539
  6. Adv Sci (Weinh). 2025 Sep 19. e09429
    NRF2-REGγ-ACADM/KLF15 Signaling Pathway Regulates the Browning of White Adipose Tissue to Modulate Obesity.
    Hui Chen, Qiujing Guan, Shuangming Gong, Yingying Du, Zhidan Zhang, Yan Liu, Lei Zhou, Lin Liu, Baoquan Xin, Yilan Guo, Hui Zhang, Ziyang Zhou, Tongchao Pei, Guohong Yu, Sokun Yin, Lei Li.
      Obesity is a significant risk factor for diabetes, cardiovascular diseases, and certain cancers, and manifests as excessive fat accumulation. The browning of white adipose tissue (WAT) represents one of the most promising strategies for preventing and treating obesity and metabolic diseases. To date, an increasing number of studies have focused on key molecular mechanisms regulating fat thermogenesis, laying the foundation for effective intervention strategies. Here, REGγ expression is shown to be significantly upregulated in adipose tissue of obese individuals and in inguinal WAT (iWAT) of obese mice. Deficiency in REGγ expression reduces fat deposition, increases energy expenditure in adipose tissue, and protects mice from HFD-induced obesity and insulin resistance. Mechanistically, REGγ expression regulates browning of WAT by modulating ACADM and KLF15-UCP1 signaling in a ubiquitin-independent degradation manner. Overactivation of the NRF2-REGγ axis facilitates adipose tissue function to cause obesity. Notably, inhibition of REGγ in the iWAT alleviates HFD-induced obesity, thereby identifying REGγ as a latent target for obesity treatment. Together, the findings provide new targets for intervening in obesity and might ultimately offer new options for treating obesity.
    Keywords:  PSME3; browning of white adipose tissue; obesity; ubiquitin‐independent protein degradation
    DOI:  https://doi.org/10.1002/advs.202509429
  7. Nat Genet. 2025 Sep 15.
    Advancing biological understanding of cellular senescence with computational multiomics.
    SenNet Consortium
      Cellular senescence is a complex biological process that plays a pathophysiological role in aging and age-related diseases. The biological understanding of senescence at the cellular and tissue levels remains incomplete due to the lack of specific biomarkers as well as the relative rarity of senescent cells, their phenotypic heterogeneity and dynamic features. This Review provides a comprehensive overview of multiomic approaches for the characterization and biological understanding of cellular senescence. The technical capability and challenges of each approach are discussed, and practical guidelines are provided for selecting tools for identifying, characterizing and spatially mapping senescent cells. The importance of computational analyses in multiomics research, including senescent cell identification, signature detection and interactions of senescent cells with microenvironments, is highlighted. Moreover, tissue-specific case studies and experimental design considerations for individual organs are presented. Finally, future directions and the potential impact of multiomic approaches on the biological understanding of cellular senescence are discussed.
    DOI:  https://doi.org/10.1038/s41588-025-02314-y
  8. Cell Rep Med. 2025 Sep 16. pii: S2666-3791(25)00381-7. [Epub ahead of print]6(9): 102308
    Can muscle avert GLP1R weight plateau and regain?
    Dongdong Wang, Andre Djalalvandi, Christina T Saed, Katherine M Morrison, Gregory R Steinberg.
      GLP1R-based obesity therapies can reduce lean muscle and energy expenditure via adaptive thermogenesis (also known as metabolic adaptation), leading to weight plateaus and regain. Defining the role of muscle energy expenditure in mediating these effects is critical to improving next-generation treatments and sustaining long-term weight loss.
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102308
  9. Sci Adv. 2025 Sep 19. 11(38): eadw9095
    Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.
    Anthony W Martinelli, Chun-Pei Wu, Tristan Vornbäumen, Hudson W Coates, Louise H Jordon, Niek Wit, Jia J Sia, Anneliese O Speak, James A Nathan.
      Cellular iron levels must be tightly regulated to ensure sufficient iron for essential enzymatic functions while avoiding the harmful generation of toxic species. Here, to better understand how iron levels are controlled, we carry out genome-wide mutagenesis screens in human cells. Alongside mapping known components of iron sensing, we determine the relative contributions of iron uptake, iron recycling, ferritin breakdown, and mitochondrial flux in controlling the labile iron pool. We also identify SETD2, a histone methyltransferase, as a chromatin modifying enzyme that controls intracellular iron availability through ferritin breakdown. Functionally, we show that SETD2 inhibition or cancer-associated SETD2 mutations render cells iron deficient, thereby driving resistance to ferroptosis and potentially explaining how some tumors evade antitumoral immunity.
    DOI:  https://doi.org/10.1126/sciadv.adw9095
  10. Trends Endocrinol Metab. 2025 Sep 12. pii: S1043-2760(25)00174-2. [Epub ahead of print]
    Metabolic hallmarks of type 2 diabetes compromise T cell function.
    Yuteng Liang, Weixin Chen, Qier Gao, Kathryn Choon-Beng Tan, Chi-Ho Lee, Guang Sheng Ling.
      Type 2 diabetes (T2D) manifests as profound systemic metabolic dysregulation. Mounting evidence indicates T2D significantly impairs T cell immunity, compromising both protective immune responses and immune homeostasis. This dysfunction stems from the multitude roles of metabolites in T cell biology: energy substrates, signaling molecules, and epigenetic regulators. In this review, we synthesize current evidence on how the metabolic hallmarks of T2D (hyperglycemia, hyperinsulinemia, and dyslipidemia) reprogram T cell metabolism and their functionalities. Notably, most patients with T2D receive combination antidiabetic therapies which not only correct systemic metabolism but also exert direct immunomodulatory effects on T cells. Unraveling the interplay between disease-driven metabolic perturbations and pharmacologically induced immunomodulation is essential to advance therapeutic strategies that restore immune competence while preserving immunoregulatory balance.
    Keywords:  T cells; immunometabolism; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.tem.2025.08.005
  11. Nat Commun. 2025 Sep 19. 16(1): 8272
    Genetic architecture of plasma metabolome in 254,825 individuals.
    Yi-Xuan Qiang, Yi-Xuan Wang, Xiao-Yu He, Yue-Ting Deng, Yi-Jun Ge, Bang-Sheng Wu, You Jia, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu.
      Circulating metabolites are crucial to biological processes underlying health and diseases, yet their genetic determinants remain incompletely understood. Here, we investigate the genetic architecture of nuclear magnetic resonance-based metabolomics, analyzing 249 metabolic measures and 64 biologically plausible ratios in 254,825 participants. We conduct a genome-wide association study (GWAS) identifying 24,438 independent variant-metabolite associations across 427 loci, with effect sizes highly concordant with 19 previous studies. Fine-mapping pinpoints 3610 putative causal associations, 785 of which are novel. Additionally, we utilize whole exome sequencing data and uncover 2948 gene-metabolite associations through aggregate testing, underscoring the importance of rare coding variants overlooked in GWAS. Integrating our findings with disease genetics reveals potential causal associations, such as between acetate levels and the risk of atrial fibrillation and flutter. Collectively, this study delineates the complex genetic architecture of the plasma metabolome, offering a valuable resource for future investigations into disease mechanisms and therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-025-62126-w
  12. Aging Adv. 2025 Sep;2(3): 108-111
    Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.
    Kit Neikirk, Suraj Thapliyal, Sepiso K Masenga, Ashton Oliver, Margaret Mungai, Han Le, Heather K Beasley, Andrea G Marshall, Anthonya T Cooper, Taneisha Gillyard Cheairs, Benjamin I Rodriguez, Edgar Garza-Lopez, Prasanna Katti, Antentor Hinton.
      Mitochondrial epigenetics, a burgeoning field bridging mitochondrial biology and epigenetic regulation, has emerged as a critical determinant of aging and age-related diseases. While nuclear epigenetics is well-characterized, the mechanisms governing mitochondrial DNA (mtDNA) regulation, including nucleoid dynamics, non-coding RNAs (ncRNAs), and metabolite-driven modifications, remain underexplored. This review synthesizes evidence that mitochondrial epigenetics influences cardiovascular pathogenesis through altered DNA methylation and histone acetylation patterns, which dysregulate oxidative phosphorylation and nucleoid stability. In neurodegenerative diseases, endoplasmic reticulum-mitochondrial contact points, disrupted by aging, impair calcium homeostasis and promote neuronal apoptosis, while oxidative stress exacerbates mtDNA instability through inefficient repair mechanisms. Cancer cells exploit mitochondrial metabolic reprogramming, where shifts in acetyl-CoA and α-ketoglutarate levels modulate epigenetic enzymes, fostering drug resistance. Potential therapeutic targets include pharmacological modulation of Mitochondrial transcription factor A acetylation/phosphorylation to enhance mtDNA transcription and dietary interventions to boost NAD+ levels, thereby improving mitochondrial function. Transgenerational studies reveal matrilineal inheritance of mtDNA methylation patterns and stress-induced epigenetic memory, though technical limitations in detecting mtDNA methylation persist. Clinically, mitochondrial epigenetic biomarkers like mtDNA hydroxymethylation and lncRNA expression (e.g., Mitoregulin) show promise for early diagnosis and treatment monitoring. Despite advances, challenges include standardizing methods for mtDNA methylation analysis and translating preclinical findings into therapies. This perspective review underscores the need for integrative approaches combining single-cell sequencing and CRISPR-based technologies to dissect mitochondrial-nuclear crosstalk, ultimately paving the way for precision medicine strategies targeting mitoepigenetic pathways to mitigate age-related decline.
    Keywords:  aging; epigenetics; methylation; mitochondria; mitochondrial nucleoid; mtDNA
    DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00006
  13. iScience. 2025 Aug 15. 28(8): 113111
    Increased levels of syndecan-3 are associated with childhood obesity.
    Diego Muñoz-Moreno, Eva Prida, Axel Y Baumann, Raquel Pérez-Lois, Miguel Bascoy, Laura Díaz-Garzón Dopico, Beatriz Brea-García, María Villalón, Rosaura Picans-Leis, Rocío Vázquez-Cobela, Ana Estany-Gestal, Luisa María Seoane, Rosaura Leis, Omar Al-Massadi, Mar Quiñones.
      Childhood obesity is considered an important risk factor for developing obesity in adult. Syndecan-3 (SDC3) has recently come into focus as a possible molecular target involved in alterations of energy homeostasis, however, its role in childhood obesity remains undefined. We measured mRNA expression levels of SDC3 in children and adolescents with obesity from peripheral blood mononuclear cells and correlating them with different anthropometric and biochemical parameters. We performed a cross-sectional study involving 143 Caucasian children and adolescents. We found increased SDC3 expression in children and adolescents with obesity. In addition, a positive statistical correlation has been found between the levels of SDC3 with body weight, BMI, BMI Z score, fat mass, waist circumference, insulin levels, HOMA-IR index, and maximum blood pressure. Finally, a multiple linear regression analysis indicated that the BMI Z score variable was the most significant. Taken together, our results highlight a still unexplored link between SDC3 and childhood obesity.
    Keywords:  Human metabolism; Pediatrics
    DOI:  https://doi.org/10.1016/j.isci.2025.113111
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