bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–11–09
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. Creatine kinase B regulates glycolysis and de novo lipogenesis pathways to control lipid accumulation during adipogenesis.
  2. Leveraging genetic and phenotypic variation to discover metabolite-protein interactions.
  3. Adipocyte death promotes hepatic infiltration of S100A8+ macrophages and steatotic liver disease progression in mice.
  4. The role of the ventromedial hypothalamus in glycemic responses.
  5. When more is not worse: Genetic subtypes of obesity challenge conventional risk paradigms.
  6. 12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat.
  7. Adipogenin promotes the development of lipid droplets by binding a dodecameric seipin complex.
  8. A unified framework for systematic curation and evaluation of aging biomarkers.
  9. Understanding the molecular basis of mesenchymal stem cell stemness: implications for clinical applications.
  10. The DMHGABA Neurons Play a Crucial Role in The Regulation of Cold-Induced White Adipose Browning through DMH to LPO Projection.
  11. Hepatic LONP1 Overexpression Ameliorates Hepatic Steatosis and Fibrosis in mice.
  12. A recurrent ACAA2 variant causes a dominant syndrome of lipodystrophy, lipomatosis, infantile steatohepatitis and hypoglycemia.
  13. Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes.
  1. Cell Rep. 2025 Nov 05. pii: S2211-1247(25)01260-4. [Epub ahead of print]44(11): 116489
    Creatine kinase B regulates glycolysis and de novo lipogenesis pathways to control lipid accumulation during adipogenesis.
    Gianluca Renzi, Romane Higos, Ivan Vlassakev, Abdoul Akim Bello, Muhmmad Omar-Hmeadi, Mattias Hansen, Fatiha Merabtene, Christine Rouault, Ondrej Hodek, Lucas Massier, Bruno Antonny, Geneviève Marcelin, Janane F Rahbani, Simon Lecoutre, Salwan Maqdasy.
      White adipocyte differentiation or adipogenesis requires coordination of metabolic sensing and transcriptional modifications to orchestrate lipid storage. Creatine and its kinases are implicated in adipose energy buffering, but the roles of cytosolic (CKB) and mitochondrial (CKMT2) creatine kinases in adipogenesis are unclear. We find that both CKB and CKMT2 are progressively upregulated during differentiation. Functional studies show that CKB restrains de novo lipogenesis (DNL) by limiting activation of carbohydrate-responsive element-binding protein (ChREBP), a key regulator of lipogenic genes. Mechanistically, CKB interacts with AKT and regulates its activation in response to insulin. Loss of CKB causes persistent AKT-mTORC1 signaling, increases glycolytic flux, and enhances ChREBP activation, thereby promoting glucose-derived lipid synthesis. Thus, CKB acts as a metabolic rheostat linking creatine-kinase activity to insulin signaling and nutrient-responsive transcription. We propose a CKB-AKT-ChREBP regulatory axis that contributes to metabolic remodeling and lipid homeostasis during adipocyte differentiation.
    Keywords:  AKT-mTORC; CKB; CP: metabolism; ChREBP; adipogenesis; creatine kinase; de novo lipogenesis; white adipocyte
    DOI:  https://doi.org/10.1016/j.celrep.2025.116489
  2. Cell Metab. 2025 Nov 04. pii: S1550-4131(25)00442-5. [Epub ahead of print]37(11): 2105-2106
    Leveraging genetic and phenotypic variation to discover metabolite-protein interactions.
    Gregory S Ducker, Jared Rutter.
      How metabolites regulate protein function is still poorly understood. Leveraging the power of genetic variation, Xiao et al. built a global protein-metabolite covariation dataset to reveal novel protein-metabolite regulations in mouse that led to the discovery of cysteine catabolism as an unexpected regulator of cholesterol.
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.008
  3. J Clin Invest. 2025 Nov 03. pii: e190635. [Epub ahead of print]135(21):
    Adipocyte death promotes hepatic infiltration of S100A8+ macrophages and steatotic liver disease progression in mice.
    Yukun Guan, Yeonsoo Kim, Yang Wang, Ye Eun Cho, Xiaogang Xiang, Seung-Jin Kim, Tiantian Yao, Dechun Feng, Seonghwan Hwang, Bin Gao.
      Both adipocytes and hepatocytes have the capacity to store fat, but the factor(s) that determine fat distribution between these cell types remain unknown. In mice fed a high-fat diet, fat initially accumulates predominantly in adipocytes, while hepatic fat accumulation mainly emerges after the onset of epididymal adipocyte death that results in elevated free fatty acids to promote lipid accumulation in hepatocytes. However, it remains unclear whether other signals after adipocyte death are required to direct and/or promote hepatocytes to store fat and subsequently trigger metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease). Using genetically modified mouse models combined with bulk and single-cell RNA-Seq analysis, we demonstrated that visceral adipocyte death induced an accumulation of S100A8+ macrophages in the liver, which was partially induced by fatty acids and apoptotic adipocyte-derived extracellular vesicles. Macrophage-specific deletion of the S100a8 gene reduced hepatic fat accumulation and MASLD severity in mice. Mechanistically, S100A8+ macrophages suppressed cellular communication network factor 3 (CCN3), a negative regulator of CD36, thereby enhancing CD36 expression in hepatocytes. In conclusion, adipocyte death promotes hepatic infiltration of S100A8+ macrophages, which drive hepatocyte lipid storage and subsequently promote MASLD progression through CD36 upregulation, partially mediated by CCN3 suppression.
    Keywords:  Adipose tissue; Gastroenterology; Hepatology; Macrophages
    DOI:  https://doi.org/10.1172/JCI190635
  4. Cell Metab. 2025 Nov 04. pii: S1550-4131(25)00438-3. [Epub ahead of print]37(11): 2097-2098
    The role of the ventromedial hypothalamus in glycemic responses.
    Kaylee Zilinger, Rachel J Perry.
      Mechanisms that preserve glucose homeostasis are highly conserved across species, with the brain playing a central role in regulating these counterregulatory responses. However, the exact neural circuits underlying this regulation remain poorly understood. The previewed papers illuminate how the ventromedial hypothalamus orchestrates glycemic responses through brain-liver communication during periods of increased glucose demand.
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.004
  5. Cell Metab. 2025 Nov 04. pii: S1550-4131(25)00436-X. [Epub ahead of print]37(11): 2099-2101
    When more is not worse: Genetic subtypes of obesity challenge conventional risk paradigms.
    Hanieh Yaghootkar.
      Emerging evidence challenges the view of obesity as a uniform metabolic risk. Spotlighting the recent Nature Medicine study by Chami et al.,1 this piece discusses how "uncoupling" adiposity from its cardiometabolic consequences reveals biologically distinct subtypes of obesity. Integrating imaging and multi-omics offers a promising path toward personalized obesity management and deeper mechanistic insight.
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.002
  6. Cell Metab. 2025 Nov 04. pii: S1550-4131(25)00479-6. [Epub ahead of print]
    12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat.
    Luiz Osório Leiria, Chih-Hao Wang, Matthew D Lynes, Kunyan Yang, Farnaz Shamsi, Mari Sato, Satoru Sugimoto, Emily Y Chen, Valerie Bussberg, Niven R Narain, Brian E Sansbury, Justin Darcy, Tian Lian Huang, Sean D Kodani, Masaji Sakaguchi, Andréa L Rocha, Tim J Schulz, Alexander Bartelt, Gökhan S Hotamisligil, Michael F Hirshman, Klaus van Leyen, Laurie J Goodyear, Matthias Blüher, Aaron M Cypess, Michael A Kiebish, Matthew Spite, Yu-Hua Tseng.
      
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.019
  7. Science. 2025 Nov 06. 390(6773): eadr9755
    Adipogenin promotes the development of lipid droplets by binding a dodecameric seipin complex.
    Chao Li, Xue-Nan Sun, Jan-Bernd Funcke, Lauri Vanharanta, Xavier Prasanna, Kaitlynn Gov, Yan Li, Megan Virostek, Chanmin Joung, Nolwenn Joffin, Kristiina Kanerva, Abel Szkalisity, Waldemar Kulig, Leon Straub, Shiuhwei Chen, Joselin Velasco, Ayanna Cobb, Davide La Padula, May-Yun Wang, Toshiharu Onodera, Csaba Vörös, Dae-Seok Kim, Min Kim, Oleg Varlamov, Yang Li, Chen Liu, Andrea R Nawrocki, Shangang Zhao, Da Young Oh, Zhao V Wang, Ruth Gordillo, Joel M Goodman, R Max Wynn, W Mike Henne, Ilpo Vattulainen, Yan Han, Elina Ikonen, Philipp E Scherer.
      The microprotein adipogenin (Adig) is predominantly expressed in adipose tissues. Here, we found that Adig interacts with seipin to form a stable, rigid complex. We present the structure of the seipin-Adig complex at an overall resolution of ~3.0 angstroms. The structure revealed that mammalian seipin assembles into two distinct oligomeric forms: undecamers and dodecamers. Adig selectively bound to the dodecameric form and enhanced seipin assembly by bridging and stabilizing adjacent subunits. Functionally, this complex promoted lipid droplet development at both early and late stages. In transgenic mice, adipocyte-specific overexpression of Adig increased fat mass and enlarged lipid droplets, whereas Adig deletion disrupted triglyceride accumulation in brown adipose tissues. Thus, Adig can modulate lipid storage through its structural and functional interactions with seipin.
    DOI:  https://doi.org/10.1126/science.adr9755
  8. Nat Aging. 2025 Nov 04.
    A unified framework for systematic curation and evaluation of aging biomarkers.
    Kejun Ying, Seth Paulson, Alec Eames, Alexander Tyshkovskiy, Siyuan Li, Nir Eynon, Macsue Jacques, Robin Grolaux, Kirsten Seale, Erik Jacques, Ludger J E Goeminne, Andrea Cipriano, Martin Perez-Guevara, Mehrnoosh Emamifar, Maximiliano Casas Martínez, Dayoon Kwon, Anna Kosheleva, Michael Snyder, Dane Gobel, Chiara Herzog, Daniel L McCartney, Riccardo E Marioni, Jessica Lasky-Su, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev.
      Aging biomarkers are essential tools for quantifying biological aging, but systematic validation has been hindered by methodological inconsistencies and fragmented datasets. Here we show that the ability of traditional aging clocks to predict chronological age does not correlate with mortality prediction capacity (R = 0.12, P = 0.67), suggesting that these metrics capture distinct biological processes. We developed Biolearn, an open-source framework enabling standardized evaluation of 39 biomarkers across over 20,000 individuals from diverse cohorts. The Horvath skin and blood clock achieved the highest chronological age accuracy (R2 = 0.88), while GrimAge2 demonstrated the strongest mortality association (hazard ratio = 2.57) and healthspan prediction (hazard ratio = 2.00). Our systematic evaluation reveals considerable heterogeneity in biomarker performance across different clinical outcomes, with optimal biomarkers varying according to specific application. Biolearn provides unified data processing pipelines with quality control and cell-type deconvolution capabilities, establishing a foundation for reproducible aging research and facilitating development of robust aging biomarkers.
    DOI:  https://doi.org/10.1038/s43587-025-00987-y
  9. Cell Death Dis. 2025 Nov 03. 16(1): 778
    Understanding the molecular basis of mesenchymal stem cell stemness: implications for clinical applications.
    Tong Ming Liu, Wikie Tew, Zheng Yang, Bing Lim, James Hoi Po Hui, Eng Hin Lee, Yuin-Han Loh, Simon Cool.
      Human mesenchymal stem cells (MSCs) have been studied in over 1500 clinical trials to treat over 30 diseases. However, the understanding towards MSC stemness remains under studied. So far, little is known about how MSCs maintain undifferentiated state or commit to specific lineages under different microenvironmental cues. The lack of comprehensive understanding regarding MSC stemness greatly hampers the translation of research findings into successful clinical application due to unclear mechanism of action. Emerging evidence shows that a variety of genetic factors delicately regulate MSC self-renewal and differentiation. In this review, we summarize the role of transcriptional factors, cell cycle regulators, genomic stability genes, cellular quality control, epigenetic regulators, non-coding RNAs, mitochondrial function, growth factors and m6A modification in regulating the stemness of MSCs. Strategies to maintain MSC stemness during ex-vivo expansion are also discussed. This review will deepen understanding of MSC stemness for advancing clinical applications and provide insights into future directions for research aimed at improving MSC-based therapies.
    DOI:  https://doi.org/10.1038/s41419-025-08094-x
  10. Adv Sci (Weinh). 2025 Nov 05. e08513
    The DMHGABA Neurons Play a Crucial Role in The Regulation of Cold-Induced White Adipose Browning through DMH to LPO Projection.
    Zhijie Su, Yujia Hou, Bingwei Wang, Qian Zhou, Wen Yang, Bingbing Guo, Chenyu Zhang, Miao Zhao, Xiaoning Yang, Jiarui Liu, Xiangyang Xie, Lihua Qin, Weiguang Zhang, Wei L Shen, Ruimao Zheng.
      The browning of white adipose tissue (WAT) can convert energy-storing WAT into energy-dissipating beige adipose tissue to combat obesity and metabolic dysfunction. Cold exposure is a WAT browning-inducing condition in mice. Hypothalamus regulates WAT browning. However, the mechanism of central regulation of WAT browning is still elusive. Here, it is reported that GABAergic neurons in the dorsomedial hypothalamus (DMHGABA neurons) are activated in response to cold exposure. Designer receptors exclusively activated by designer drugs (DREADDs) activation of DMHGABA neurons elicited WAT browning, increased energy expenditure, lowered fat mass weights, and body weight. Conversely, inactivation of DMHGABA neurons showed the opposite effects. Cell type-specific anterograde tracing revealed that DMHGABA neurons projected to the lateral preoptic area (LPO). Chemogenetic and optogenetic functional circuit interrogation demonstrated that the activation of this projection induced WAT browning. Together, it is uncovered that DMHGABA neurons may act as a key neuronal population controlling cold exposure-induced WAT browning. DMHGABA neurons regulate WAT browning through DMH to LPO projection. This study expands the understanding of the central mechanism governing the white adipose browning, as well as the anti-obesity effects of cold therapy.
    Keywords:  GABAergic neurons; cold exposure; dorsomedial hypothalamus; lateral preoptic area; white adipose tissue browning
    DOI:  https://doi.org/10.1002/advs.202508513
  11. J Hepatol. 2025 Oct 31. pii: S0168-8278(25)02607-8. [Epub ahead of print]
    Hepatic LONP1 Overexpression Ameliorates Hepatic Steatosis and Fibrosis in mice.
    Monan Liu, Meijie Chen, Jianping Weng, Suowen Xu.
      
    DOI:  https://doi.org/10.1016/j.jhep.2025.10.024
  12. J Clin Invest. 2025 Nov 04. pii: e198888. [Epub ahead of print]
    A recurrent ACAA2 variant causes a dominant syndrome of lipodystrophy, lipomatosis, infantile steatohepatitis and hypoglycemia.
    Vinaya Simha, Mary Kate LoPiccolo, Anna Platt, Rebecca J Brown, Xandria Johnson, Deanna Alexis Carere, Colleen Donnelly, Matthew T Snyder, Chao Xing, Thomas P Mathews, Purva Gopal, Stephen C Ward, Diana R Tomchick, Anil K Agarwal, Ralph J DeBerardinis, Abhimanyu Garg.
      
    Keywords:  Adipose tissue; Diabetes; Endocrinology; Genetic diseases; Genetics
    DOI:  https://doi.org/10.1172/JCI198888
  13. Nat Commun. 2025 Nov 04. 16(1): 9492
    Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes.
    Yuta Yanagihara, Masatomo Takahashi, Yoshihiro Izumi, Tomofumi Kinoshita, Masaki Takao, Takeshi Bamba, Yuuki Imai.
      Chondrocytes differentiated from mesenchymal stem cells play a role in determining skeletal patterns by ossification. However, the mechanism by which maintenance DNA methylation in chondrocytes regulates differentiation and skeletal formation is unclear. In the Musculoskeletal Knowledge Portal, Dnmt1 is significantly associated with Height. Long bones in Dnmt1-deficient (Dnmt1ΔPrx1) mouse limbs are significantly shortened due to decreased chondrocyte proliferation and accelerated differentiation. Integrated analysis of RNA-Seq and MBD-Seq reveals that reduced DNA methylation in Dnmt1ΔPrx1 chondrocytes leads to increased expression of genes related to energy metabolism and to ossification. Metabolomic analyses confirm that Dnmt1ΔPrx1 chondrocytes had increased levels of nearly all energy metabolites. These results indicate that Dnmt1-mediated maintenance of DNA methylation governs chondrocyte differentiation by regulating energy metabolism through both gene expression and modulation of metabolite supplies. Taken together, this study suggests that appropriate DNA methylation status in chondrocytes can orchestrate growth plate mineralization and subsequently determine bone length.
    DOI:  https://doi.org/10.1038/s41467-025-65145-9
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