bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–03–02
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. What makes biological age epigenetic clocks tick.
  2. Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice.
  3. Chchd10: A Novel Metabolic Sensor Modulating Adipose Tissue Homeostasis.
  4. Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling.
  5. Multiomic QTL mapping reveals phenotypic complexity of GWAS loci and prioritizes putative causal variants.
  6. Nuclear factor erythroid 2-related factor 2 ameliorates disordered glucose and lipid metabolism in liver: Involvement of gasdermin D in regulating pyroptosis.
  7. Human genomic regions of systemic interindividual epigenetic variation are implicated in neurodevelopmental and metabolic disorders.
  8. Adipocyte Septin-7 attenuates obesogenic adipogenesis and promotes lipolysis to prevent obesity.
  9. DNA hypermethylation-induced suppression of ALKBH5 is required for folic acid to alleviate hepatic lipid deposition by enhancing autophagy in an ATG12-dependent manner.
  10. Deep Learning Derived Adipocyte Size Reveals Adipocyte Hypertrophy is under Genetic Control.
  11. Cooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis.
  12. ALKBH3-Mediated M1A Demethylation of METTL3 Endows Pathological Fibrosis:Interplay Between M1A and M6A RNA Methylation.
  13. Peripheral fat mobilization and mitochondrial fat metabolism: Fueling the energy demands of liver regeneration.
  1. Nat Aging. 2025 Feb 24.
    What makes biological age epigenetic clocks tick.
    Mahdi Moqri, Jesse R Poganik, Steve Horvath, Vadim N Gladyshev.
      
    DOI:  https://doi.org/10.1038/s43587-025-00833-1
  2. iScience. 2025 Feb 21. 28(2): 111903
    Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice.
    Han Wang, Lizi Zhang, Xing Chen, Lingzi Hong, Junjie Zhao, Wen Qian, Lam Khue Pham, Belinda Willard, Xiaoxia Li, Katarzyna Bulek, Xiao Li.
      Six-transmembrane protein of prostate 4 (Steap4), highly expressed in adipose tissue, is associated with metabolic homeostasis. Dysregulated adipose and mitochondrial metabolism contributes to obesity, highlighting the need to understand their interplay. Whether and how Steap4 influences mitochondrial function, adipocytes, and energy expenditure remain unclear. Adipocyte-specific Steap4-deficient mice exhibited increased fat mass and severe insulin resistance in our high-fat diet model. Mass spectrometry identified two classes of Steap4 interactomes: mitochondrial proteins and proteins involved in splicing. RNA sequencing (RNA-seq) analysis of white adipose tissue demonstrated that Steap4 deficiency altered RNA splicing patterns with enriched mitochondrial functions. Indeed, Steap4 deficiency impaired respiratory chain complex activity, causing mitochondrial dysfunction in white adipose tissue. Consistently, brown adipocyte-specific Steap4 deficiency impaired mitochondrial function, increased brown fat whitening, reduced energy expenditure, and exacerbated insulin resistance in a high-fat model. Overall, our study highlights Steap4's critical role in modulating adipocyte mitochondrial function, thereby controlling thermogenesis, energy expenditure, and adiposity.
    Keywords:  Biological sciences; Endocrinology; Natural sciences; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2025.111903
  3. Adv Sci (Weinh). 2025 Feb 22. e2408763
    Chchd10: A Novel Metabolic Sensor Modulating Adipose Tissue Homeostasis.
    Xiaoping Wu, Zixuan Zhang, Jingjing Li, Jiuyu Zong, Lufengzi Yuan, Lingling Shu, Lai Yee Cheong, Xiaowen Huang, Mengxue Jiang, Zhihui Ping, Aimin Xu, Ruby L C Hoo.
      Dysregulation of adipose tissue (AT) homeostasis in obesity contributes to metabolic stress and disorders. Here, we identified that Coiled-coil-helix-coiled-coil-helix domain containing 10 (Chchd10) is a novel regulator of AT remodeling upon excess energy intake. Chchd10 is significantly reduced in the white adipose tissue (WAT) of mice in response to high-fat diet (HFD) feeding. AT-Chchd10 deficiency accelerates adipogenesis predominantly in subcutaneous AT of mice to store excess energy in response to short-term HFD feeding while upregulates glutathione S-transferase A4 (GSTA4) to facilitate 4-HNE clearance mainly in visceral AT to prevent protein carbonylation-induced cell dysfunction after long-term HFD feeding. Hence, Chchd10 deficiency attenuates diet-induced obesity and related metabolic disorders in mice. Mechanistically, Chchd10 deficiency enhances adipogenesis and GSTA4 expression by activating TDP43/Raptor/p62/Keap1/NRF2 axis. Notably, the beneficial effect of Chchd10 deficiency is eliminated in hypertrophic adipocytes, where p62 is strikingly reduced. Collectively, Chchd10 is a metabolic sensor maintaining AT homeostasis, and the loss of p62 in adipose tissue under obese conditions impairs Chchd10-mediated AT remodeling.
    Keywords:  Chchd10; GSTA4; NRF2; TDP43; adipogenesis; adipose tissue remodeling; obesity; p62; protein carbonylation
    DOI:  https://doi.org/10.1002/advs.202408763
  4. Science. 2025 Feb 28. 387(6737): eadp4120
    Liver ALKBH5 regulates glucose and lipid homeostasis independently through GCGR and mTORC1 signaling.
    Kaixin Ding, Zhipeng Zhang, Zhengbin Han, Lei Shi, Xinzhi Li, Yutong Liu, Zhenzhi Li, Chongchong Zhao, Yifeng Cui, Liying Zhou, Bolin Xu, Wenjing Zhou, Yikui Zhao, Zhiqiang Wang, He Huang, Liwei Xie, Xiao-Wei Chen, Zheng Chen.
      Maintaining glucose and lipid homeostasis is crucial for health, with dysregulation leading to metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated fatty liver disease (MAFLD). This study identifies alkylation repair homolog protein 5 (ALKBH5), an RNA N6-methyladenosine (m6A) demethylase, as a major regulator in metabolic disease. ALKBH5 is up-regulated in the liver during obesity and also phosphorylated by protein kinase A, causing its translocation to the cytosol. Hepatocyte-specific deletion of Alkbh5 reduces glucose and lipids by inhibiting the glucagon receptor (GCGR) and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. Targeted knockdown of hepatic Alkbh5 reverses T2DM and MAFLD in diabetic mice, highlighting its therapeutic potential. This study unveils a regulatory mechanism wherein ALKBH5 orchestrates glucose and lipid homeostasis by integrating the GCGR and mTORC1 pathways, providing insight into the regulation of metabolic diseases.
    DOI:  https://doi.org/10.1126/science.adp4120
  5. Cell Genom. 2025 Feb 16. pii: S2666-979X(25)00031-X. [Epub ahead of print] 100775
    Multiomic QTL mapping reveals phenotypic complexity of GWAS loci and prioritizes putative causal variants.
    iPSCORE Consortium
      Most GWAS loci are presumed to affect gene regulation; however, only ∼43% colocalize with expression quantitative trait loci (eQTLs). To address this colocalization gap, we map eQTLs, chromatin accessibility QTLs (caQTLs), and histone acetylation QTLs (haQTLs) using molecular samples from three early developmental-like tissues. Through colocalization, we annotate 10.4% (n = 540) of GWAS loci in 15 traits by QTL phenotype, temporal specificity, and complexity. We show that integration of chromatin QTLs results in a 2.3-fold higher annotation rate of GWAS loci because they capture distal GWAS loci missed by eQTLs, and that 5.4% (n = 13) of GWAS colocalizing eQTLs are early developmental specific. Finally, we utilize the iPSCORE multiomic QTLs to prioritize putative causal variants overlapping transcription factor motifs to elucidate the potential genetic underpinnings of 296 GWAS-QTL colocalizations.
    Keywords:  GWAS; QTLs; chromatin accessibility QTLs; expression QTLs; histone acetylation QTLs; iPSC-derived cardiovascular progenitors; iPSC-derived pancreatic precursors; induced pluripotent stem cells; multiomic QTLs; quantitative trait loci
    DOI:  https://doi.org/10.1016/j.xgen.2025.100775
  6. Clin Transl Med. 2025 Mar;15(3): e70233
    Nuclear factor erythroid 2-related factor 2 ameliorates disordered glucose and lipid metabolism in liver: Involvement of gasdermin D in regulating pyroptosis.
    Xuyun Xia, Qin Zhang, Xia Fang, Ling Li, Gangyi Yang, Xiaohui Xu, Mengliu Yang.
       BACKGROUND: The epidemic of metabolic dysfunction-associated fatty liver disease linked to excessive high-fat diet (HFD) consumption has sparked widespread public concern. Nuclear factor erythroid 2-related factor 2 (NRF2) has been reported to improve glucose/lipid metabolism, liver lipid degeneration and alleviate HFD-induced inflammation. However, its pathways and mechanisms of action are not fully understood.
    METHODS: To confirm the effect of NRF2 on glucose/lipid metabolism in the liver, Nrf2-/- mice as well as liver-specific Nrf2 knockout mice, and AAV-TBG-Nrf2 were employed. The hyperinsulinemic-euglycemic clamp was utilized to determine the effect of NRF2 on glucose metabolism. To elucidate the effect of NRF2 on pyroptosis, we performed western blots, immunofluorescence, quantitative real-time PCR, and Flow cytometry experiments. Finally, chromatin immunoprecipitation-seq and dual-luciferase reporter assay was used to underscore the transcriptional regulatory effect of NRF2 on Gsdmd.
    RESULTS: We found that overexpression of Nrf2 inhibited the expression of inflammatory cytokines and pyroptosis markers, including cle-Caspase1, NLRP3 and the N-terminus of gasdermin D (N-GSDMD) both in vivo and in vitro, while Nrf2 deficiency was the opposite. Specifically, with NRF2 expression up-regulated, GSDMD expression decreased and Gsdmd overexpression partially reversed the effect of Nrf2 overexpression on pro-inflammatory phenotype. Mechanistically, we demonstrate that NRF2 binds to the Gsdmd promoter at the -2110 - 1130 bp site, inhibiting the GSDMD expression and thereby improving glucose/lipid metabolism and liver steatosis.
    CONCLUSION: Our data indicate that NRF2 is an effective inhibitor of pyroptosis and has a multi-target effect in the treatment of obesity-related metabolic diseases.
    KEY POINTS: MAFLD is associated with increased hepatocytes NRF2 expression. NRF2 alleviates MAFLD by suppressing pyroptosis. NRF2 directly inhibits GSDMD expression to regulate pyroptosis. Targeting the NRF2-pyroptosis (GSDMD) axis offers a potential therapeutic strategy for MAFLD.
    Keywords:  GSDMD; NRF2; glucose/lipid metabolism; pyroptosis
    DOI:  https://doi.org/10.1002/ctm2.70233
  7. medRxiv. 2025 Feb 12. pii: 2025.02.10.25322021. [Epub ahead of print]
    Human genomic regions of systemic interindividual epigenetic variation are implicated in neurodevelopmental and metabolic disorders.
    Wen-Jou Chang, Uditha Maduranga, Chathura J Gunasekara, Alan Yang, Matthew Hirschtritt, Katrina Rodriguez, Cristian Coarfa, Goo Jun, Craig L Hanis, James M Flanagan, Ivan P Gorlov, Christopher I Amos, Joseph L Wiemels, Catherine A Schaefer, Ezra S Susser, Robert A Waterland.
      Epigenome-wide association studies (EWAS) profile DNA methylation across the human genome to identify associations with diseases and exposures. Most employ Illumina methylation arrays; this platform, however, under-samples interindividual epigenetic variation. The systemic and stable nature of epigenetic variation at correlated regions of systemic interindividual variation (CoRSIVs) should be advantageous to EWAS. Here, we analyze 2,203 published EWAS to determine whether Illumina probes within CoRSIVs are over-represented in the literature. Enrichment of CoRSIV-overlapping probes was observed for most classes of disease, particularly for neurodevelopmental disorders and type 2 diabetes, indicating an opportunity to improve the power of EWAS by over 200- and over 100-fold, respectively. EWAS targeting all known CoRSIVs should accelerate discovery of associations between individual epigenetic variation and risk of disease.
    DOI:  https://doi.org/10.1101/2025.02.10.25322021
  8. Mol Metab. 2025 Feb 25. pii: S2212-8778(25)00021-3. [Epub ahead of print] 102114
    Adipocyte Septin-7 attenuates obesogenic adipogenesis and promotes lipolysis to prevent obesity.
    Liran Xu, Chao Yang, Kaidan Pang, Ying Zhang, Yu He, Siyu Liu, Huijing Tian, Zehua Shao, Siyu Wang, Xingqian Liu, Ting Li, Yapeng Cao, Luqin Yan, Jinjin Liu, Yanan Wang, Yongxin Li, Wei Zhao, Youhua Wang, Yang Yan, Shengpeng Wang.
       OBJECTIVE: The white adipose tissue (WAT) expansion plays a significant role in the development of obesity. Cytoskeletal remodeling directly impacts adipogenic program, however, the precise mechanism remains poorly understood. Here, we identified a crucial role of Septin-7 (SEPT7), a cytoskeleton component, in the regulation of diet-induced processes of adipogenesis, lipogenesis, and lipolysis in WAT.
    METHODS: A high-fat diet (HFD)-induced obesity model was constructed using mice with inducible adipocyte-specific SEPT7 deficiency. The impact of SEPT7 on adipocyte morphology, cell number and metabolism capacity were evaluated with immunofluorescence, isoproterenol induced lipolysis assay, glucose tolerance test and insulin tolerance test. Adipocyte mTmG reporter line was established to trace in vivo adipogenesis. The preadipocyte 3T3-L1 cell was induced for exploring role of SEPT7 in adipocyte differentiation. qRT-PCR and Western-blot were used to investigate the expression of PPARγ, C/EBPα, and HSL in 3T3-L1 cell with siRNA-mediated SEPT7 knockdown.
    RESULTS: SEPT7 expression was greatly induced in obesogenic human and murine adipocytes. Mice lacking SEPT7 in mature white adipocytes demonstrated defective differentiation of preadipocyte into mature adipocytes when fed HFD resulting in larger adipocytes, increased WAT inflammation and reduced lipolysis, which leading to increased WAT mass, liver fat accumulation and impaired glucose tolerance. Mechanistically, we identified SEPT7 restrains store-operated Ca2+ entry (SOCE) and regulates adipocyte adipogenesis and lipolysis by targeting PPARγ, C/EBPα and HSL.
    CONCLUSION: We demonstrated that SEPT7 negatively regulates adipogenesis while promotes lipolysis and its repression drives WAT expansion and impaired metabolic health.
    Keywords:  Septin-7; adipocyte; adipogenensis; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2025.102114
  9. J Nutr Biochem. 2025 Feb 22. pii: S0955-2863(25)00033-6. [Epub ahead of print] 109870
    DNA hypermethylation-induced suppression of ALKBH5 is required for folic acid to alleviate hepatic lipid deposition by enhancing autophagy in an ATG12-dependent manner.
    Chaoqun Huang, Yaojun Luo, Youhua Liu, Jiaqi Liu, Yushi Chen, Botao Zeng, Xing Liao, Yuxi Liu, Xinxia Wang.
      Nonalcoholic fatty liver disease (NAFLD) occurs when too much fat builds up in the liver. As a growing worldwide epidemic, NAFLD is strongly linked with multiple metabolic diseases including obesity, insulin resistance, and dyslipidemia. However, very few effective treatments are currently available. Folate, an essential B-group vitamin with important biological functions including DNA and RNA methylation regulation, has been shown to have a protective effect against NAFLD with its underlying mechanism remains largely unclear. Here, we show that administration of folic acid significantly improves glucose tolerance, insulin sensitivity, and dyslipidemia in high-fat diet (HFD) fed mice. Moreover, folic acid treatment significantly inhibits lipid deposition in hepatocytes both in vivo and in vitro. Mechanically, folic acid reduces the expression of m6A demethylase AlkB homolog 5 (ALKHB5) via promoter DNA hypermethylation. Decreased ALKBH5 causes increased m6A modification and increased expression of ATG12 in a demethylase activity-dependent manner, thereby promoting autophagy and preventing hepatic steatosis. Inhibition of ATG12 induced by overexpression of ALKBH5 could impair autophagy and the inhibitory effect of folic acid on lipid accumulation in hepatocytes. Together, these findings provide novel insights into understanding the protective role of folic acid in the treatment of NAFLD and suggest that folic acid may be a potential agent for combating NAFLD.
    Keywords:  Autophagy; Folic acid; Lipid metabolism; Methylation; NAFLD
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.109870
  10. medRxiv. 2025 Feb 12. pii: 2025.02.11.25322053. [Epub ahead of print]
    Deep Learning Derived Adipocyte Size Reveals Adipocyte Hypertrophy is under Genetic Control.
    Emil Jørsboe, Phil Kubitz, Julius Honecker, Andrea Flaccus, Dagmar Mvondo, Matthias Raggi, Torben Hansen, Hans Hauner, Matthias Blüher, Philip D Charles, Cecilia M Lindgren, Christoffer Nellåker, Melina Claussnitzer.
      Fat distribution and macro structure of white adipose tissue are important factors in predicting obesity-associated diseases, but cellular microstructure of white adipose tissue has been less explored. To investigate the relationship between adipocyte size and obesity-related traits, and their underlying disease-driving genetic associations, we performed the largest study of automatic adipocyte phenotyping linking histological measurements and genetics to date. We introduce deep learning based methods for scalable and accurate semantic segmentation of subcutaneous and visceral adipose tissue histology samples (N=2,667) across 5 independent cohorts, including data from 9,000 whole slide images, with over 27 million adipocytes. Estimates of mean size of adipocytes were validated against Glastonbury et al. 2020. We show that adipocyte hypertrophy correlates with an adverse metabolic profile with increased levels of leptin, fasting plasma glucose, glycated hemoglobin and triglycerides, and decreased levels of adiponectin and HDL cholesterol. We performed the largest GWAS (N Subcutaneous = 2066, N Visceral = 1878) and subsequent meta-analysis of mean adipocyte area, and find two genome-wide significant loci (rs73184721, rs200047724) associated with increased 95%-quantile adipocyte size in respectively visceral and subcutaneous adipose tissue. Stratifying by sex, in females we find two genome-wide significant loci, with one variant (rs140503338) associated with increased mean adipocyte size in subcutaneous adipose tissue, and the other (rs11656704) is associated with decreased 95%-quantile adipocyte size in visceral adipose tissue.
    DOI:  https://doi.org/10.1101/2025.02.11.25322053
  11. Nat Commun. 2025 Feb 22. 16(1): 1890
    Cooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis.
    Ziyu Sun, Jianyu Ye, Weimin Sun, Libo Jiang, Bing Shan, Mengmeng Zhang, Jingyi Xu, Wanjin Li, Jianping Liu, Hongyang Jing, Tian Zhang, Meiling Hou, Cen Xie, Rongling Wu, Heling Pan, Junying Yuan.
      Dysfunctional NF-κB signaling is critically involved in inflammatory bowel disease (IBD). We investigated the mechanism by which RIPK1 and TRADD, two key mediators of NF-κB signaling, in mediating intestinal pathology using TAK1 IEC deficient model. We show that phosphorylation of TRADD by TAK1 modulates RIPK1-dependent apoptosis. TRADD and RIPK1 act cooperatively to mediate cell death regulated by TNF and TLR signaling. We demonstrate the pathological evolution from RIPK1-dependent ileitis to RIPK1- and TRADD-co-dependent colitis in TAK1 IEC deficient condition. Combined RIPK1 inhibition and TRADD knockout completely protect against intestinal pathology and lethality in TAK1 IEC KO mice. Furthermore, we identify distinctive microbiota dysbiosis biomarkers for RIPK1-dependent ileitis and TRADD-dependent colitis. These findings reveal the cooperation between RIPK1 and TRADD in mediating cell death and inflammation in IBD with NF-κB deficiency and suggest the possibility of combined inhibition of RIPK1 kinase and TRADD as a new therapeutic strategy for IBD.
    DOI:  https://doi.org/10.1038/s41467-025-57211-z
  12. Adv Sci (Weinh). 2025 Feb 28. e2417067
    ALKBH3-Mediated M1A Demethylation of METTL3 Endows Pathological Fibrosis:Interplay Between M1A and M6A RNA Methylation.
    Liying Tu, Shuchen Gu, Ruoqing Xu, En Yang, Xin Huang, Hsin Liang, Shenying Luo, Haizhou Li, Yixuan Zhao, Tao Zan.
      Epigenetic modifications serve as crucial molecular switches for pathological fibrosis; howbeit the role of m1A in this condition remains enigmatic. Herein, it is found that ALKBH3 exerts a pro-fibrotic effect in pathological skin fibrosis by reshaping N6-methyladenosine (m6A) RNA modification pattern. First, ALKBH3 exhibited specific upregulation within hypertrophic scars (HTS), accompanied by N1-methyladenosine (m1A) hypomethylation. Moreover, multiomics analyses identified METTL3, a critical writer enzyme involved in m6A modification, as a downstream candidate target of ALKBH3. Therapeutically, ablation of ALKBH3 inhibited the progression of HTS both in vitro and in vivo, while exogenous replenishment of METTL3 counteracted this antifibrotic effect. Mechanistically, ALKBH3 recognizes the m1A methylation sites and prevents YTHDF2-dependent mRNA decay of METTL3 transcript. Subsequently, METTL3 stabilizes collagen type I alpha 1 chain (COL1A1) and fibronectin1 (FN1) mRNAs, two major components of extracellular matrix, and therefore eliciting the pathological transformation of HTS. This observation bridges the understanding of the link between m1A and m6A methylation, the two fundamental RNA modifications, underscoring the participation of "RNA methylation crosstalk" in pathological events.
    Keywords:  ALKBH3; METTL3; RNA methylation; fibroblast; pathological skin fibrosis
    DOI:  https://doi.org/10.1002/advs.202417067
  13. J Hepatol. 2025 Feb 27. pii: S0168-8278(25)00071-6. [Epub ahead of print]
    Peripheral fat mobilization and mitochondrial fat metabolism: Fueling the energy demands of liver regeneration.
    Cornelius Engelmann.
      
    DOI:  https://doi.org/10.1016/j.jhep.2025.01.034
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