bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–10–05
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.
  2. Novel Function of Osteoprotegerin in the Modulation of Glucose Metabolism in the Liver via mTORC1.
  3. cGAS Inhibits ALDH2 to Suppress Lipid Droplet Function and Regulate MASLD Progression.
  4. Cold-season programming reinforces the brown fat-cardiometabolic health link.
  5. Pan-tissue transcriptome analysis reveals sex-dimorphic human aging.
  6. Polygenic risk score for type 2 diabetes shows context-dependent effects across populations.
  7. The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.
  8. Clonal hematopoiesis driven by Dnmt3a mutations promotes metabolic disease development in mice.
  9. Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
  10. GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling.
  11. A genetic map of human metabolism across the allele frequency spectrum.
  12. GDF15 regulates development and growth of sympathetic neurons to enhance energy expenditure and thermogenesis.
  13. Leptin: 30 Years Later.
  1. Nat Commun. 2025 Oct 03. 16(1): 8831
    MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.
    Chunyan Wu, Tongtong Wang, Adhideb Ghosh, Fen Long, Anand Kumar Sharma, Tina Dahlby, Falko Noé, Ilenia Severi, Georgia Colleluori, Saverio Cinti, Antonio Giordano, Lianggong Ding, Radhika Khandelwal, Sarantos Kostidis, Martin Giera, Lucia Balazova, Vincent Gardeux, Laith Abu-Nawwas, Bart Deplancke, Sabita Chourasia, Sandra Kleiner, Bradford S Hamilton, Juan Manuel Alcántara Alcántara, Jonatan R Ruiz, Matthias Blüher, Anton Pekcec, Miroslav Balaz, Atan Gross, Heike Neubauer, Christian Wolfrum.
      Metabolic disorders, including obesity and metabolic-associated steatohepatitis, arise from a chronic energy surplus. Thus, enhancing energy dissipation through increased respiration holds significant therapeutic potential for metabolic disorders. Through a comprehensive analysis of human and murine adipose tissues, along with a functional screen, we identify mitochondrial carrier homolog 2, a mitochondrial outer membrane protein, as a pivotal regulator of mitochondrial metabolism. Intriguingly, its expression in adipose tissue is a strong determinant of obesity in humans. Adipocyte-specific ablation of mitochondrial carrier homolog 2 improves mitochondrial function and whole-body energy expenditure, independent of uncoupling protein 1. Furthermore, mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction, leading to enhanced energy expenditure in adipocytes/adipose tissue. Here we show mitochondrial carrier homolog 2 functions as a negative regulator of energy metabolism in adipocytes and represents a potential target for treating obesity and related metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-025-63880-7
  2. Diabetes. 2025 Sep 30. pii: db250207. [Epub ahead of print]
    Novel Function of Osteoprotegerin in the Modulation of Glucose Metabolism in the Liver via mTORC1.
    Sheng Qiu, Xia Wang, Ke Li, Siliang Zhang, Yerui Lai, Qiao Mi, Min Yang, Dongfang Liu, Ling Li, Qinan Wu, Mengliu Yang.
       ARTICLE HIGHLIGHTS: Methylation of the Opg promoter inhibits hepatic OPG expression in obese mice. Hepatic OPG regulates glucose metabolism and insulin sensitivity in obese mice. OPG regulates glucose metabolism through interaction with mammalian target of rapamycin complex 1 (Raptor). Opg deficiency in mice reduces age-related metabolic dysfunction.
    DOI:  https://doi.org/10.2337/db25-0207
  3. Adv Sci (Weinh). 2025 Oct 03. e08576
    cGAS Inhibits ALDH2 to Suppress Lipid Droplet Function and Regulate MASLD Progression.
    Ying Wang, Yu Deng, Jianfeng Chen, Quentin Hahn, David S Umbaugh, Zhigang Zhang, Yanqiong Zhang, Sarah E Rowe, Lupeng Li, Laura E Herring, Brian P Conlon, Edward A Miao, Blossom Damania, Anna Mae Diehl, Pengda Liu.
      Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor essential for host defense against microbial infections, but its role beyond innate immunity remains unclear. Here, a non-canonical function of cGAS in regulating aldehyde metabolism and lipid homeostasis is identified. This is demonstrated that cGAS directly binds to and suppresses ALDH2 (aldehyde dehydrogenase 2), a key enzyme in ethanol metabolism and lipid peroxidation. Loss of cGAS activates ALDH2, thereby enhancing ethanol tolerance in mice. Elevated ALDH2 activity upon cGAS loss increases aldehyde conversion into acetyl-CoA, promoting histone acetylation and transcription of lipid synthesis genes, which drives lipid droplet accumulation in cells and in cGas-/- mouse livers. These lipid droplets confer resistance to ferroptosis but simultaneously induce ER stress, impairing STING (stimulator of interferon genes) activation. Functionally, cGas-/- mice fed with a modified high-fat diet develop exacerbated metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by excessive lipid droplet accumulation in livers compared to wild-type controls. In human MASLD patient cohorts, increased cGAS but reduced ALDH2 mRNA expression is observed relative to healthy individuals. Together, this findings uncover a previously unrecognized role of cGAS in metabolic regulation, independent of its innate immune function. By suppressing ALDH2, cGAS controls lipid droplet biogenesis and stress responses, with direct implications for MASLD pathogenesis.
    Keywords:  ALDH2; HFD; MASLD; cGAS; lipid droplets
    DOI:  https://doi.org/10.1002/advs.202508576
  4. Trends Endocrinol Metab. 2025 Sep 27. pii: S1043-2760(25)00199-7. [Epub ahead of print]
    Cold-season programming reinforces the brown fat-cardiometabolic health link.
    Taylah L Gaynor, Camilla Scheele.
      Recent work by Yoneshiro et al. links brown adipose tissue (BAT) activity to environmental temperatures during conception, highlighting intergenerational influences shaping BAT function. Here we explore how these findings translate into a cardiometabolic health phenotype and discuss how it can be mediated through sperm epigenetic programming.
    DOI:  https://doi.org/10.1016/j.tem.2025.09.007
  5. Elife. 2025 Oct 03. pii: RP102449. [Epub ahead of print]13
    Pan-tissue transcriptome analysis reveals sex-dimorphic human aging.
    Siqi Wang, Danyue Dong, Xin Li, Zefeng Wang.
      Complex diseases often exhibit sex dimorphism in morbidity and prognosis, many of which are age-related. However, the underlying mechanisms of sex-dimorphic aging remain foggy, with limited studies across multiple tissues. We systematically analyzed ~17,000 transcriptomes from 35 human tissues to quantitatively evaluate the individual and combined contributions of sex and age to transcriptomic variations. We discovered extensive sex dimorphisms during aging with distinct patterns of change in gene expression and alternative splicing (AS). Intriguingly, the male-biased age-associated AS events have a stronger association with Alzheimer's disease, and the female-biased events are often regulated by several sex-biased splicing factors that may be controlled by estrogen receptors. Breakpoint analysis showed that sex-dimorphic aging rates are significantly associated with decline of sex hormones, with males having a larger and earlier transcriptome change. Collectively, this study uncovered an essential role of sex during aging at the molecular and multi-tissue levels, providing insight into sex-dimorphic regulatory patterns.
    Keywords:  AS regulatory network; aging; alternative splicing; chromosomes; computational biology; gene expression; human; sex dimorphism; systems biology; time series
    DOI:  https://doi.org/10.7554/eLife.102449
  6. Nat Commun. 2025 Oct 01. 16(1): 8632
    Polygenic risk score for type 2 diabetes shows context-dependent effects across populations.
    biobank at the Colorado Center for Personalized Medicine (CCPM)
      Polygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traits and type 2 diabetes complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between type 2 diabetes and other diseases. These findings highlight the need to account for context when evaluating polygenic risk score as a tool for type 2 diabetes risk prognostication and the potentially generalizable associations of type 2 diabetes polygenic risk score with diabetes-related traits, despite differential performance in type 2 diabetes prediction across diverse populations. Our study provides a comprehensive resource to characterize a type 2 diabetes polygenic risk score.
    DOI:  https://doi.org/10.1038/s41467-025-63546-4
  7. Sci Adv. 2025 Oct 03. 11(40): eadw7376
    The PP2A-B55α phosphatase is a master regulator of mitochondrial degradation and biogenesis.
    Valentina Cianfanelli, Monica Nanni, Samantha Corrà, Sofia Mauri, David Sumpton, Sergio Lilla, Rossella De Cegli, Matteo Bordi, Giacomo Milletti, Caterina Ferraina, Arnaldur Hall, Michele Petraroia, Valentina Clausi, Ezio Giorda, Marco Scarsella, Alessandra Barbiera, Giulia Cadeddu, Marco Colasanti, Tiziana Persichini, Kenji Maeda, Apolinar Maya-Mendoza, Jiri Bartek, Chiara Di Malta, Franco Locatelli, Sara Zanivan, Shehab Ismail, Elena Ziviani, Francesco Cecconi.
      Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number. Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the insult, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS. PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.
    DOI:  https://doi.org/10.1126/sciadv.adw7376
  8. J Clin Invest. 2025 Sep 30. pii: e197100. [Epub ahead of print]
    Clonal hematopoiesis driven by Dnmt3a mutations promotes metabolic disease development in mice.
    Bowen Yan, Qingchen Yuan, Marco M Buttigieg, Prabhjot Kaur, Annalisse R McKee, Daniil E Shabashvili, Caitlyn Vlasschaert, Alexander G Bick, Michael J Rauh, Olga A Guryanova.
      
    Keywords:  Diabetes; Hematology; Inflammation; Metabolism; Mouse models; Obesity
    DOI:  https://doi.org/10.1172/JCI197100
  9. Nat Commun. 2025 Sep 30. 16(1): 8685
    Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
    Sirikrishna Thatavarthy, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Kelly E Zuccaro, Akhil Gargey Iragavarapu, Gabriela May Sullivan, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.
      Cardiolipin is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which cardiolipin influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics simulations, we determined that cardiolipin molecules extensively engage with the paddle domain of mitochondrial fusion protein OPA1, which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between cardiolipin and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled cardiolipin probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the cardiolipin brominated lipid bilayers. Our images provide direct evidence of cardiolipin enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin. This suggests that the partial replacement of cardiolipin by monolyso-cardiolipin, as observed in Barth syndrome, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-63813-4
  10. Science. 2025 Oct 02. 390(6768): eads8728
    GCN1 couples GCN2 to ribosomal state to initiate amino acid response pathway signaling.
    Changqian Zhou, Miao Zhang, Jason Murray, Joao Paulo, Steve Gygi, Sichen Shao, Malcolm Whitman, Tracy Keller.
      During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stresses. GCN2 activation has been linked to its association with uncharged tRNAs, specific ribosomal proteins, and conditions of translational arrest, but their relative contribution to activation is unclear. Here, we used in vitro translation to reconstitute GCN2 activation by amino acid stress and compared collided ribosome populations induced by diverse translational stressors. Initiation of GCN2 signaling required the di-ribosome sensor GCN1, which recruits GCN2 to ribosomes in a collision-dependent manner, where GCN2 becomes activated by key ribosomal interactions and stably associated with collided ribosomes. Our findings define the molecular requirements and dynamics of GCN2 activation.
    DOI:  https://doi.org/10.1126/science.ads8728
  11. Nat Genet. 2025 Oct 03.
    A genetic map of human metabolism across the allele frequency spectrum.
    Martijn Zoodsma, Carl Beuchel, Summaira Yasmeen, Leonhard Kohleick, Aakash Nepal, Mine Koprulu, Florian Kronenberg, Manuel Mayr, Alice Williamson, Maik Pietzner, Claudia Langenberg.
      Genetic studies of human metabolism have been limited in scale and allelic breadth. Here we provide a data-driven map of the genetic regulation of circulating small molecules and lipoprotein characteristics (249 traits) measured using proton nuclear magnetic resonance spectroscopy across the allele frequency spectrum in ~450,000 individuals. Trans-ancestral meta-analyses identify 29,824 locus-metabolite associations mapping to 753 regions with effects largely consistent between men and women and large ancestral groups represented in UK Biobank. We observe and classify extreme genetic pleiotropy, identify regulators of lipid metabolism, and assign effector genes at >100 loci through rare-to-common allelic series. We propose roles for genes less established in metabolic control (for example, SIDT2), genes characterized by phenotypic heterogeneity (for example, APOA1) and genes with specific disease relevance (for example, VEGFA). Our study demonstrates the value of broad, large-scale metabolomic phenotyping to identify and characterize regulators of human metabolism.
    DOI:  https://doi.org/10.1038/s41588-025-02355-3
  12. Exp Mol Med. 2025 Oct 01.
    GDF15 regulates development and growth of sympathetic neurons to enhance energy expenditure and thermogenesis.
    Jinyoung Kim, Annie Zhao, Seo Hyun Park, Jaeseok Han, Deok-Hyeon Cheon, Sang-Hyeon Ju, Yoonhyuk Jang, Kon Chu, Hyung Jin Choi, Jiyoon Kim, Myung-Shik Lee.
      Growth differentiation factor 15 (GDF15) induces weight loss and increases sympathetic activity through its receptor GFRAL. Given that RET, a GFRAL coreceptor, influences neuronal growth, we studied whether GDF15 can induce the development or growth of sympathetic neurons, in addition to its effect on sympathetic activity. Here we we used GDF15-transgenic and Gdf15-knockout mice to explore the role of GDF15 in the development and activity of sympathetic neurons. GDF15-transgenic mice exhibited increased surface area and volume of sympathetic neurite in adipose tissues. Furthermore, these mice showed heightened energy expenditure, thermogenesis, cold tolerance and an elevated sympathetic response to hypoglycemia. GFRAL was expressed in sympathetic ganglion cells, which was enhanced by GDF15. RET and its downstream signaling molecules such as AKT, ERK and CREB were activated in the sympathetic ganglia by transgenic expression of GDF15 in vivo or treatment with GDF15 in vitro, an leading to increased expression of genes related to thermogenesis, neurite growth or extension and catecholamine synthesis. An ex vivo treatment of sympathetic ganglia with GDF15 also promoted neurite growth and extension. By contrast, Gdf15-knockout mice showed opposite phenotypes, underscoring the physiological role of GDF15 in the development and activity of the sympathetic nervous system. These findings indicate that GDF15 regulates not only the sympathetic activity but also the development or growth of sympathetic neurons through GFRAL expressed in sympathetic ganglion cells, which could contribute to energy expenditure and weight loss. The modulation of GDF15 could be a therapeutic option against diseases or conditions associated with dysregulated sympathetic activity.
    DOI:  https://doi.org/10.1038/s12276-025-01543-9
  13. Annu Rev Physiol. 2025 Oct 03.
    Leptin: 30 Years Later.
    Rexford S Ahima, Jeffrey S Flier.
      The discovery of leptin as an adipocyte-secreted hormone encoded by the ob gene whose absence produces severe obesity that is corrected by leptin repletion in both mice and humans was a transformative event in metabolic science. Leptin's discovery in 1994 accelerated the identification of central neuronal circuitry responsive to peripheral signals that regulate energy balance as well as metabolic, neuroendocrine, and other vital functions. Leptin's primary physiological role was initially viewed as preventing obesity by its levels rising, but subsequent research has emphasized the key role of falling levels to signal starvation. Resistance to leptin action, though partial, characterizes common forms of obesity. Despite much being learned about leptin signal transduction over 30 years, the precise molecular mechanisms for leptin resistance and common obesity remain unclear. Leptin therapy is effective in rare patients with congenital leptin deficiency and other low leptin conditions but not common obesity. Interestingly, reducing hyperleptinemia may prove useful in treating common obesity.
    DOI:  https://doi.org/10.1146/annurev-physiol-042324-100259
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