bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–02–23
twelve papers selected by
Xiong Weng, University of Edinburgh
  1. RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
  2. Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK.
  3. Loss of VSTM2A promotes adipocyte hypertrophy and disrupts metabolic homeostasis.
  4. Dnmt3b deficiency in adipocyte progenitor cells ameliorates obesity in female mice.
  5. Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
  6. Adenosine Monophosphate Improves Lipolysis in Obese Mice by Reducing DNA Methylation via ADORA2A Activation by Ecto-5'-Nucleotidase (CD73).
  7. The autophagy receptor Ncoa4 controls PPARγ activity and thermogenesis in brown adipose tissue.
  8. Mitochondrial and Stress-Related Psychobiological Regulation of FGF21 in Humans.
  9. METTL3-catalyzed m6A methylation facilitates the contribution of vascular smooth muscle cells to atherosclerosis.
  10. Melanocortin 3 receptor regulates hepatic autophagy and systemic adiposity.
  11. Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
  12. Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation.
  1. Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00013-0. [Epub ahead of print]
    RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
    Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman.
      Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.
    Keywords:  PGC1α; adipocyte; adipose thermogenesis; adipose tissue; cGAS-STING; inflammation; mRNA translation; mitochondria; obesity; oxidative metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.013
  2. Nat Commun. 2025 Feb 18. 16(1): 1738
    Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK.
    Chang Peng, Haowen Jiang, Liya Jing, Wenhua Yang, Xiaotong Guan, Hanlin Wang, Sike Yu, Yutang Cao, Min Wang, Huan Ma, Zan Lv, Hongyu Gu, Chunmei Xia, Xiaozhen Guo, Bin Sun, Aili Wang, Cen Xie, Wenbiao Wu, Luyiyi Lu, Jiayi Song, Saifei Lei, Rui Wu, Yi Zang, Erjiang Tang, Jia Li.
      Obesity is regarded as a chronic inflammatory disease involving adipose tissue macrophages (ATM), but whether immunometabolic reprogramming of ATM affects obesity remains unclarified. Here we show that in ATM glutaminolysis is the fundamental metabolic flux providing energy and substrate, bridging with AMP-activated protein kinase (AMPK) activity, succinate-induced interleukin-1β (IL-1β) production, and obesity. Abrogation of AMPKα in myeloid cells promotes proinflammatory ATM, impairs thermogenesis and energy expenditure, and aggravates obesity in mice fed with high-fat diet (HFD). Conversely, IL-1β neutralization or myeloid IL-1β abrogation prevents obesity caused by AMPKα deficiency. Mechanistically, ATP generated from glutaminolysis suppresses AMPK to decrease phosphorylation of the β subunit of succinyl-CoA synthetase (SUCLA2), thereby resulting in the activation of succinyl-CoA synthetase and the overproduction of succinate and IL-1β; by contrast, siRNA-mediated SUCLA2 knockdown reduces obesity induced by HFD in mice. Lastly, phosphorylated SUCLA2 in ATM correlates negatively with obesity in humans. Our results thus implicate a glutaminolysis/AMPK/SUCLA2/IL-1β axis of inflammation and obesity regulation in ATM.
    DOI:  https://doi.org/10.1038/s41467-025-57044-w
  3. Obesity (Silver Spring). 2025 Feb 16.
    Loss of VSTM2A promotes adipocyte hypertrophy and disrupts metabolic homeostasis.
    Manal Al Dow, Blandine Secco, Mathilde Mouchiroud, Marianne Rochette, Gustavo R Gilio, Mickael Massicard, Marilou Hardy, Yves Gélinas, William T Festuccia, Mathieu C Morissette, Venkata S K Manem, Mathieu Laplante.
       OBJECTIVE: Adipose tissue expands through hyperplasia and hypertrophy to store excess lipids, a process that is essential for the maintenance of metabolic homeostasis. The mechanisms regulating adipocyte recruitment from progenitors remain unclear. We have previously identified V-set and transmembrane domain-containing protein 2A (VSTM2A) as a factor promoting fat cell development in vitro. Whether VSTM2A impacts adipose tissue and systemic metabolism in vivo is still unknown.
    METHODS: We generated VSTM2A knockout mice (Vstm2a-/-) using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) and fed them either a chow or high-fat diet. These mice were evaluated for body weight, adiposity, blood parameters, and glucose homeostasis.
    RESULTS: Vstm2a-/- mice were viable and showed no body weight differences. Although adipose mass was similar, Vstm2a-/- mice had larger adipocytes, an effect linked to inflammation, ectopic lipid deposition, and impaired glucose and lipid metabolism. Transcriptomic analysis revealed that VSTM2A loss affects the expression of several genes in adipose tissue, including some related to the lysosome. Interestingly, acute lysosomal inhibition early in life is sufficient to cause adipocyte hypertrophy in adults.
    CONCLUSIONS: VSTM2A is dispensable for adipose tissue formation, but its loss causes adipocyte hypertrophy and impairs glucose and lipid homeostasis. Our study also underscores a critical role of the lysosome in initiating adipogenesis.
    DOI:  https://doi.org/10.1002/oby.24224
  4. bioRxiv. 2025 Feb 02. pii: 2025.01.31.635994. [Epub ahead of print]
    Dnmt3b deficiency in adipocyte progenitor cells ameliorates obesity in female mice.
    Yifei Huang, Sean Yu, Qiang Cao, Jia Jing, Weiqing Tang, Bingzhong Xue, Hang Shi.
      Obesity arises from chronic energy imbalance where energy intake exceeds energy expenditure. Emerging evidence supports a key role of DNA methylation in the regulation of adipose tissue development and metabolism. We recently discovered a key role of DNA methylation, catalyzed by DNA methyltransferase 1 or 3a (Dnmt1 or 3a), in the regulation of adipocyte differentiation and metabolism. Here, we aimed to investigate the role of adipocyte progenitor cell Dnmt3b, an enzyme mediating de novo DNA methylation, in energy metabolism and obesity. We generated a genetic model with Dnmt3b knockout in adipocyte progenitor cells (PD3bKO) by crossing Dnmt3b -floxed mice with platelet-derived growth factor receptor alpha (Pdgfrα)-Cre mice. Dnmt3b gene deletion in adipocyte progenitors enhanced thermogenic gene expression in brown adipose tissue, increased overall energy expenditure, and mitigated high-fat diet (HFD)-induced obesity in female mice. PD3bKO mice also displayed a lower respiratory exchange ratio (RER), indicative of a metabolic shift favoring fat utilization as an energy source. Furthermore, female PD3bKO mice exhibited improved insulin sensitivity alongside their lean phenotype. In contrast, male PD3bKO mice showed no changes in body weight but demonstrated decreased insulin sensitivity, revealing a sexually dimorphic metabolic response to Dnmt3b deletion in adipocyte progenitor cells. These findings underscore the critical role of Dnmt3b in regulating energy homeostasis, body weight, and metabolic health, with significant implications for understanding sex-specific mechanisms of obesity and metabolism.
    DOI:  https://doi.org/10.1101/2025.01.31.635994
  5. Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00024-5. [Epub ahead of print]
    Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
    Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Amanda L Smythers, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Joao A Paulo, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.
      Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.
    Keywords:  MPST; ergothioneine; exercise; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.024
  6. Adv Sci (Weinh). 2025 Feb 20. e2405079
    Adenosine Monophosphate Improves Lipolysis in Obese Mice by Reducing DNA Methylation via ADORA2A Activation by Ecto-5'-Nucleotidase (CD73).
    Zhijuan Cui, Li Feng, Sujuan Rao, Zihao Huang, Shuangbo Huang, Liudan Liu, Yuan Liao, Zheng Lan, Qiling Chen, Jinping Deng, Leli Wang, Yulong Yin, Chengquan Tan.
      The previous work discovers the potential of adenosine monophosphate (AMP) to alleviate obesity-related metabolic diseases, but the underlying molecular mechanisms remain incompletely understood. Here, AMP is confirmed to enhance white fat decomposition and improve abnormal glucose and lipid metabolism in mice fed with a high-fat (HF) diet. Mechanically, AMP is converted to adenosine (ADO) through ecto-5'-nucleotidase (CD73), and adenosine A2A receptor (ADORA2A) signaling activation is involved in the down-regulation of methylation in white adipose tissue, thereby reducing the hormone-sensitive lipase (HSL) methylation level and promoting HSL transcription and white fat decomposition. Moreover, the metabolic benefits of AMP are found to be partially eliminated in ADORA2A knockout mice, but re-expression of ADORA2A can reproduce the AMP-induced metabolic regulation in white fat. These findings reveal the mechanism that AMP, as the upstream of ADO, stimulates ADORA2A signaling and white fat DNA methylation to participate in the anti-obesity effect.
    Keywords:  ADORA2A; DNA methylation; adenosine monophosphate; ecto‐5′‐nucleotidase; obesity
    DOI:  https://doi.org/10.1002/advs.202405079
  7. bioRxiv. 2025 Feb 02. pii: 2025.02.02.636110. [Epub ahead of print]
    The autophagy receptor Ncoa4 controls PPARγ activity and thermogenesis in brown adipose tissue.
    Leslie A Rowland, Kaltinaitis B Santos, Adilson Guilherme, Sean Munroe, Lawrence M Lifshitz, Sarah Nicoloro, Hui Wang, Matthew F Yee, Michael P Czech.
      Adipose tissue dysfunction leads to a variety of deleterious systemic consequences including ectopic lipid deposition and impaired insulin sensitivity. PPARγ is a major regulator of adipocyte differentiation and functionality and is thus a determinant of systemic metabolic health. We recently reported that deletion of adipocyte fatty acid synthase (AdFasnKO) impairs autophagy in association with a striking upregulation of genes controlled by PPARγ, including thermogenic uncoupling protein 1 (Ucp1). In this present study, screening for PPARγ coactivators regulated by autophagy revealed a protein denoted as Nuclear receptor coactivator 4 (Ncoa4), known to mediate ferritinophagy and interact with PPARγ and other nuclear receptors. Indeed, we found Ncoa4 is upregulated in the early phase of adipocyte differentiation and is required for adipogenesis. Ncoa4 is also elevated in FasnKO adipocytes and necessary for full upregulation of Ucp1 expression in vitro , even in response to norepinephrine. Consistent with these findings, adipose-selective knockout of Ncoa4 (AdNcoa4KO mice) impairs Ucp1 expression in brown adipose tissue and cold-induced thermogenesis. Adipose-selective double KO of Fasn plus Ncoa4 (AdFasnNcoa4DKO mice) prevents the upregulation of classic PPARγ target genes normally observed in the white adipose tissue of AdFasnKO mice, but not thermogenic Ucp1 expression. These findings reveal Ncoa4 is a novel determinant of adipocyte PPARγ activity and regulator of white and brown adipocyte biology and suggest that manipulation of autophagy flux modulates PPARγ activity and key adipocyte functions via Ncoa4 actions.
    DOI:  https://doi.org/10.1101/2025.02.02.636110
  8. medRxiv. 2025 Feb 03. pii: 2025.01.30.25321437. [Epub ahead of print]
    Mitochondrial and Stress-Related Psychobiological Regulation of FGF21 in Humans.
    Mangesh Kurade, Natalia Bobba-Alves, Catherine Kelly, Alexander Behnke, Quinn Conklin, Robert-Paul Juster, Michio Hirano, Caroline Trumpff, Martin Picard.
      FGF21 is a metabolic hormone induced by fasting, metabolic stress, and mitochondrial oxidative phosphorylation (OxPhos) defects that cause mitochondrial diseases (MitoD). Here we report that acute psychosocial stress alone (without physical exertion) decreases serum FGF21 by an average of 20% ( p <0.0001) in healthy controls but increases FGF21 by 32% ( p <0.0001) in people with MitoD-pointing to a functional interaction between the stress response and OxPhos capacity in regulating FGF21. We further define co-activation patterns between FGF21 and stress-related neuroendocrine hormones and report novel associations between FGF21 and psychosocial factors related to stress and wellbeing, highlighting a potential role for FGF21 in meeting the energetic needs of acute and chronic psychosocial stress.
    DOI:  https://doi.org/10.1101/2025.01.30.25321437
  9. Cardiovasc Res. 2025 Feb 20. pii: cvaf029. [Epub ahead of print]
    METTL3-catalyzed m6A methylation facilitates the contribution of vascular smooth muscle cells to atherosclerosis.
    Zhigang Dong, Yourong Jin, Yicong Shen, Jiaqi Huang, Jiaai Tan, Qianqian Feng, Ze Gong, Shirong Zhu, Huiyue Chen, Fang Yu, Wei Li, Yiting Jia, Wei Kong, Yi Fu.
       AIMS: Vascular smooth muscle cells (VSMCs) are involved in the etiology of atherosclerosis, but whether methyltransferase-like 3 (METTL3)-catalyzed N6-methyladenosine (m6A) modulates the contribution of VSMCs to atherosclerosis remains elusive.
    METHODS AND RESULTS: We generated tamoxifen-inducible VSMC-specific METTL3 knockout mice with VSMC lineage tracing, and found that VSMC-specific METTL3 deficiency substantially attenuated atherosclerosis and reduced the proportion of VSMCs in plaques, due to the inhibition of VSMC atheroprone phenotype as characterized by macrophage-like and inflammatory features as well as high migratory and proliferative capacity. m6A-methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with polysome profiling analysis mechanistically displayed METTL3 catalyzed m6A methylation of myocardin-related transcription factor A (MRTFA) mRNA, and further enhanced YTH N6-methyladenosine RNA binding protein F3 (YTHDF3)-dependent MRTFA mRNA translation. Conversely, adenovirus or adeno-associated virus-mediated VSMC-specific MRTFA overexpression abolished METTL3 deficiency-mediated alleviation of VSMC atheroprone phenotypic switching and atherosclerotic progression both in vitro and in vivo.
    CONCLUSION: METTL3 facilitated the contribution of VSMCs to atherosclerosis through the m6A-YTHDF3-dependent MRTFA mRNA translation enhancement.
    Keywords:  RNA methyltransferase METTL3; atherosclerosis; phenotypic switching; vascular smooth muscle cell
    DOI:  https://doi.org/10.1093/cvr/cvaf029
  10. Nat Commun. 2025 Feb 16. 16(1): 1690
    Melanocortin 3 receptor regulates hepatic autophagy and systemic adiposity.
    Tushar P Patel, Joo Yun Jun, Arnold Y Seo, Noah J Levi, Diana M Elizondo, Jocelyn Chen, Adrian M Wong, Nicol Tugarinov, Elizabeth K Altman, Daniel B Gehle, Sun Min Jung, Pooja Patel, Mark Ericson, Carrie Haskell-Luevano, Tamar C Demby, Antony Cougnoux, Anna Wolska, Jack A Yanovski.
      Systemic lipid homeostasis requires hepatic autophagy, a major cellular program for intracellular fat recycling. Here, we find melanocortin 3 receptor (MC3R) regulates hepatic autophagy in addition to its previously established CNS role in systemic energy partitioning and puberty. Mice with Mc3r deficiency develop obesity with hepatic triglyceride accumulation and disrupted hepatocellular autophagosome turnover. Mice with partially inactive human MC3R due to obesogenic variants demonstrate similar hepatic autophagic dysfunction. In vitro and in vivo activation of hepatic MC3R upregulates autophagy through LC3II activation, TFEB cytoplasmic-to-nuclear translocation, and subsequent downstream gene activation. MC3R-deficient hepatocytes had blunted autophagosome-lysosome docking and lipid droplet clearance. Finally, the liver-specific rescue of Mc3r was sufficient to restore hepatocellular autophagy, improve hepatocyte mitochondrial function and systemic energy expenditures, reduce adipose tissue lipid accumulation, and partially restore body weight in both male and female mice. We thus report a role for MC3R in regulating hepatic autophagy and systemic adiposity.
    DOI:  https://doi.org/10.1038/s41467-025-56936-1
  11. bioRxiv. 2025 Jan 31. pii: 2025.01.28.635306. [Epub ahead of print]
    Blood mitochondrial health markers cf-mtDNA and GDF15 in human aging.
    Caroline Trumpff, Qiuhan Huang, Jeremy Michelson, Cynthia C Liu, David Shire, Christian G Habeck, Yaakov Stern, Martin Picard.
      Altered mitochondria biology can accelerate biological aging, but scalable biomarkers of mitochondrial health for population studies are lacking. We examined two potential candidates: 1) cell-free mitochondrial DNA (cf-mtDNA), a marker of mitochondrial signaling elevated with disease states accessible as distinct biological entities from plasma or serum; and 2) growth differentiation factor 15 (GDF15), an established biomarker of biological aging downstream of mitochondrial energy transformation defects and stress signaling. In a cohort of 430 participants aged 24-84 (54.2% women), we measured plasma and serum cf-mtDNA, and plasma GDF15 levels at two timepoints 5 years apart, then assessed their associations with age, BMI, diabetes, sex, health-related behaviors, and psychosocial factors. As expected, GDF15 showed a positive, exponential association with age (r=0.66, p<0.0001) and increased by 33% over five years. cf-mtDNA was not correlated with GDF15 or age. BMI and sex were also not related to cf-mtDNA nor GDF15. Type 2 diabetes was only positively associated with GDF15. Exploring potential drivers of systemic mitochondrial stress signaling, we report a novel association linking higher education to lower age-adjusted GDF15 (r=-0.14, p<0.0034), both at baseline and the 5-year follow up, highlighting a potential influence of psychosocial factors on mitochondrial health. Overall, our findings among adults spanning six decades of lifespan establish associations between age, diabetes and GDF15, an emerging marker of mitochondrial stress signaling. Further studies are needed to determine if the associations of blood GDF15 with age and metabolic stress can be moderated by psychosocial factors or health-related behaviors.
    DOI:  https://doi.org/10.1101/2025.01.28.635306
  12. Cell Metab. 2025 Feb 07. pii: S1550-4131(25)00006-3. [Epub ahead of print]
    Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation.
    Weijie Wu, Wenhai Sui, Sizhe Chen, Ziheng Guo, Xu Jing, Xiaolu Wang, Qun Wang, Xinshuang Yu, Wenjing Xiong, Jiansong Ji, Libo Yang, Yuan Zhang, Wenjing Jiang, Guohua Yu, Shuzhen Liu, Wei Tao, Chen Zhao, Yun Zhang, Yuguo Chen, Cheng Zhang, Yihai Cao.
      Consumption of artificial sweeteners (ASWs) in various foods and beverages has been linked to an increased risk of cardiovascular diseases (CVDs). However, molecular mechanisms underlying ASW-associated CVD remain unknown. Here, we show that consumption of 0.15% aspartame (APM) markedly increased insulin secretion in mice and monkeys. Bilateral subdiaphragmatic vagotomy (SDV) obliterated APM-elevated blood insulin levels, demonstrating crucial roles of parasympathetic activation in regulation of insulin secretion. Incessant APM feeding of ApoE-/- mice aggravated atherosclerotic plaque formation and growth via an insulin-dependent mechanism. Implantation of an insulin-slow-release pump in ApoE-/- mice exacerbated atherosclerosis. Whole-genome expression profiling discovered that CX3CL1 chemokine was the most upregulated gene in the insulin-stimulated arterial endothelial cells. Specific deletion of a CX3CL1 receptor, Cx3cr1 gene, in monocytes/macrophages completely abrogated the APM-exacerbated atherosclerosis. Our findings uncover a novel mechanism of APM-associated atherosclerosis and therapeutic targeting of the endothelial CX3CL1-macrophage CX3CR1 signaling axis provides an approach for treating atherosclerotic CVD.
    Keywords:  artificial sweetener; aspartame; atherosclerosis; cardiovascular disease; chemokine; insulin; insulin resistance; macrophage; stroke; vascular inflammation
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.006
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