bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–11–23
eleven papers selected by
Xiong Weng, University of Edinburgh
  1. Induction of yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice.
  2. Endothelial senescent-cell-specific clearance alleviates metabolic dysfunction in obese mice.
  3. Purinergic adipocyte-macrophage crosstalk promotes degeneration of thermogenic brown adipose tissue.
  4. An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
  5. The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.
  6. Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration.
  7. Polygenic risk score and cluster-based analysis suggests links between type 2 diabetes and vascular dementia in the KARE study.
  8. Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice.
  9. Regulation of m6A methylation in the immune microenvironment in the development of diabetes mellitus.
  10. Gut microbiome-adipose crosstalk modulates soluble IL-6 receptor influencing exercise responsiveness in glycemic control and insulin sensitivity.
  11. Mitochondrial variation in Taiwan Biobank reveals ancestry structure and trait associations.
  1. Metabolism. 2025 Nov 18. pii: S0026-0495(25)00308-7. [Epub ahead of print] 156439
    Induction of yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice.
    Line Pedersen, Christy M Gliniak, Thomas Myhre Dale, Qingzhang Zhu, Chao Li, Jan-Bernd Funcke, Clair Crewe, Jiahui Luo, Lauren Palluth, Yi Zhu, Philipp E Scherer.
      The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of Yy1 in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.
    Keywords:  Adipogenesis; Adipose tissue; Obesity; White adipose tissue; YY1
    DOI:  https://doi.org/10.1016/j.metabol.2025.156439
  2. Cell Metab. 2025 Nov 20. pii: S1550-4131(25)00443-7. [Epub ahead of print]
    Endothelial senescent-cell-specific clearance alleviates metabolic dysfunction in obese mice.
    Masayoshi Suda, Selim Chaib, Larissa G P Langhi Prata, Yi Zhu, Utkarsh Tripathi, Karl H Paul, Allyson K Palmer, Tamar Pirtskhalava, Vagisha Kulshreshtha, Christina L Inman, Kurt O Johnson, Nino Giorgadze, Runqing Huang, Carolyn M Roos, Luisa F Leon-Sanchez, Jordan D Miller, Thomas White, Linshan Laux, Laura J Niedernhofer, Paul D Robbins, Sara Espinoza, Nicolas Musi, Sundeep Khosla, Stefan G Tullius, Tamar Tchkonia, James L Kirkland.
      Accumulation of senescent cells is a key contributor to multiple diseases across the lifespan, including metabolic dysfunction. We previously demonstrated that elimination of senescent cells using senolytic drugs alleviates obesity-induced metabolic dysfunction. However, the contribution of senescent endothelial cells to metabolic disorders remains elusive. Hence, we crossed mice that allow selective elimination of senescent cells (p16Ink4a-LOX-ATTAC mice) with Tie2-Cre mice (Tie2-Cre;p16Ink4a-LOX-ATTAC) to enable identification and inducible, selective elimination of p16Ink4a+ senescent endothelial cells. Targeted removal of senescent endothelial cells from obese Tie2-Cre;p16Ink4a-LOX-ATTAC mice attenuated the pro-inflammatory senescence-associated secretory phenotype and alleviated metabolic dysfunction. Conversely, transplanting senescent endothelial cells into lean mice caused adipose tissue inflammation and metabolic dysfunction. Consistent with these findings, the senolytic, fisetin, which targets senescent endothelial cells among other senescent cell types, reduced adipose tissue senescent endothelial cell abundance and improved glucose metabolism in obese mice or mice transplanted with senescent mouse endothelial cells. Our results indicate that specifically eliminating p16Ink4a+ senescent endothelial cells is a potential therapeutic strategy for metabolic disease.
    Keywords:  SASP factors; TNFα; cellular senescence; diabetes; endothelial cells; fisetin; glucose intolerance; obesity; p16(Ink4a); senolytics
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.009
  3. EMBO Rep. 2025 Nov 19.
    Purinergic adipocyte-macrophage crosstalk promotes degeneration of thermogenic brown adipose tissue.
    Michelle Y Jaeckstein, Alexander W Fischer, Björn Rissiek, Tobias Staehler, Markus Heine, Janina Behrens, Oliver Mann, Alexander Pfeifer, Tim Magnus, Christian Schlein, Anna Worthmann, Ludger Scheja, Friedrich Koch-Nolte, Joerg Heeren.
      Loss of brown adipose tissue (BAT) activity observed during ageing, obesity and living at thermoneutrality is associated with lipid accumulation, fibrosis and tissue inflammation in BAT. The mechanisms that promote this degenerative process of BAT remain largely enigmatic. Here, we show that an imbalance between sympathetic activation and mitochondrial energy handling causes BAT degeneration, which leads to impaired energy expenditure and systemic metabolic disturbances. Mechanistically, we demonstrate that brown adipocytes secrete ATP in response to imbalanced thermogenic activation, which activates P2X4 and P2X7 of BAT-resident macrophages. Notably, mice lacking activity of these purinergic receptors in myeloid cells are protected against BAT inflammation, thermogenic dysfunction and systemic metabolic disturbances under conditions of imbalanced BAT activation, thermoneutrality or overnutrition. These results highlight the relevance of extracellular ATP released by brown adipocytes as a paracrine signal for myeloid cells to initiate BAT degeneration.
    Keywords:  Adaptive Thermogenesis; Dyslipidemia; Hyperglycemia; Inflammation; P2X Receptors
    DOI:  https://doi.org/10.1038/s44319-025-00642-y
  4. Nat Commun. 2025 Nov 20. 16(1): 10222
    An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
    Eloïse Marques, Stephen P Burr, Alva M Casey, Richard J Stopforth, Chak Shun Yu, Keira Turner, Dane M Wolf, Marisa Dilucca, Vincent Paupe, Suvagata Roy Chowdhury, Victoria J Tyrrell, Robbin Kramer, Yamini M Kanse, Chinmayi Pednekar, Chris A Powell, James B Stewart, Julien Prudent, Michael P Murphy, Michal Minczuk, Valerie B O'Donnell, Clare E Bryant, Patrick F Chinnery, Arthur Kaser, Alexander von Kriegsheim, Dylan G Ryan.
      Impaired mitochondrial bioenergetics in macrophages promotes hyperinflammatory cytokine responses, but whether inherited mtDNA mutations drive similar phenotypes is unknown. Here, we profiled macrophages harbouring a heteroplasmic mitochondrial tRNAAla mutation (m.5019A>G) to address this question. These macrophages exhibit combined respiratory chain defects, reduced oxidative phosphorylation, disrupted cristae architecture, and compensatory metabolic adaptations in central carbon metabolism. Upon inflammatory activation, m.5019A>G macrophages produce elevated type I interferon (IFN), while exhibiting reduced pro-inflammatory cytokines and oxylipins. Mechanistically, suppression of pro-IL-1β and COX2 requires autocrine IFN-β signalling. IFN-β induction is biphasic: an early TLR4-IRF3 driven phase, and a later response involving mitochondrial nucleic acids and the cGAS-STING pathway. In vivo, lipopolysaccharide (LPS) challenge of m.5019A>G mice results in elevated type I IFN signalling and exacerbated sickness behaviour. These findings reveal that a pathogenic mtDNA mutation promotes an imbalanced innate immune response, which has potential implications for the progression of pathology in mtDNA disease patients.
    DOI:  https://doi.org/10.1038/s41467-025-65023-4
  5. Mitochondrion. 2025 Nov 16. pii: S1567-7249(25)00096-0. [Epub ahead of print] 102099
    The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.
    Jakob D Busch, Thomas Schöndorf, Dusanka Milenkovic, Xinping Li, Rolf Wibom, Joana F Silva-Rodrigues, Roberta Filograna, Camilla Koolmeister, Nils-Göran Larsson, Diana Rubalcava-Gracia.
      The mitochondrial cytochrome c oxidase (COX, complex IV), a multi-subunit protein complex, plays a crucial role in cellular respiration by reducing oxygen to water and simultaneously pumping protons to enable oxidative phosphorylation (OXPHOS). Thus, defects in its assembly can directly affect cellular energy homeostasis. COX20 is an essential chaperone for the core subunit COX2. In human cultured cells, TMEM177 was found to stabilize COX20 and maintain balanced COX2 levels. In mice, TMEM177 was also identified as an interactor of mitochondrial ribosomes. To understand the function of TMEM177 in vivo, we generated Tmem177 knockout mice. Here, we analyze how TMEM177 loss affects mitochondrial gene expression, as well as the activity and assembly of OXPHOS complexes. We found that a small proportion of the knockout mice died perinatally, while surviving knockout mice tended to gain less weight. TMEM177 depletion moderately reduced COX20 levels, but OXPHOS complexes were preserved. Moreover, Tmem177 and Surf1 double knockout mice were born asymptomatic. In conclusion, TMEM177 fine-tunes complex IV assembly by stabilizing COX20 in vivo. Our findings refine the current model of complex IV assembly in mammals.
    Keywords:  Cytochrome c oxidase; Mitochondria; Mitoribosomes; OXPHOS; mtDNA
    DOI:  https://doi.org/10.1016/j.mito.2025.102099
  6. Nat Metab. 2025 Nov 20.
    Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration.
    Sarmistha Mukherjee, Ricardo A Velázquez Aponte, Caroline E Perry, Won Dong Lee, Kevin A Janssen, Marc Niere, Gabriel K Adzika, Mu-Jie Lu, Hsin-Ru Chan, Xiangyu Zou, Beishan Chen, Nicole Bye, Teresa Xiao, Jin-Seon Yook, Oniel Salik, David W Frederick, Ryan B Gaspar, Khanh V Doan, James G Davis, Joshua D Rabinowitz, Douglas C Wallace, Nathaniel W Snyder, Shingo Kajimura, Xiaolu A Cambronne, Mathias Ziegler, Joseph A Baur.
      Nicotinamide adenine dinucleotide (NAD+) precursor supplementation shows metabolic and functional benefits in rodent models of disease and is being explored as potential therapeutic strategy in humans. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down the mechanisms of action. Here we show that the rate of liver regeneration is closely associated with the concentration of NAD+ in hepatocyte mitochondria. We find that the mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1). The heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, whereas the hepatocyte-specific overexpression of SLC25A51 is sufficient to enhance liver regeneration comparably to the effect of systemic NAD+ precursor supplements. This benefit is observed even though NAD+ levels are increased only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration.
    DOI:  https://doi.org/10.1038/s42255-025-01408-5
  7. Nat Commun. 2025 Nov 19. 16(1): 10135
    Polygenic risk score and cluster-based analysis suggests links between type 2 diabetes and vascular dementia in the KARE study.
    Wanqing Dong, Zijian Tian, Jie Bai, Benrui Wu, Mengjie Zhao, Yingyu Zhang, Jian Shao, Tian Xie, Qian Li, Peng Wu, Jingnan Xue, Ying Chen, Xiaozhou Zhou, Yuxuan Du, Shiteng Gao, Haonan Pan, Anjie Peng, Ying Pan, Kaixin Zhou, Hongwei Jiang.
      Type 2 diabetes is an established risk factor for dementia. However, how its genetic heterogeneity affects different dementia subtypes remains unclear. In this study, we investigate the associations between genetic risk of type 2 diabetes and dementia subtypes among 33,136 older Chinese adults from the KARE cohort. We find that a higher overall polygenic risk score for type 2 diabetes is significantly associated with an increased risk of vascular dementia, but not Alzheimer's disease. Further analyses using cluster-specific partitioned polygenic score show that elevated genetic risk specific to the hyperinsulinemia pathway is strongly associated with increased incidence of vascular dementia. These findings highlight the potential role of insulin-related metabolic abnormalities in the pathogenesis of vascular dementia and provide genetic evidence to support the use of the hyperinsulinaemia pathway as a clinically relevant marker for early risk stratification and precision prevention strategies.
    DOI:  https://doi.org/10.1038/s41467-025-65252-7
  8. bioRxiv. 2025 Oct 02. pii: 2025.09.30.679563. [Epub ahead of print]
    Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice.
    Daniel Ferguson, Elise I Gadson, Kathleen R Markan, Jun Yoshino, Maxwell Lin, Mohammad Habibi, Snigdha Tiash, Xiaoxia Cui, Evguenia Kouranova, Edziu Franczak, Qiuyuan Guo, Jill Kealing, Terri A Pietka, Kim H H Liss, John P Thyfault, Gary J Patti, Brian N Finck, Clair Crewe, Sandip Mukherjee.
      Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme and a central factor in energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) maintains the cellular NAD+ pool by synthesizing the NAD+ precursor, nicotinamide mononucleotide (NMN), and diminished adipocyte NAMPT activity has been implicated in aging- and obesity-related metabolic dysfunction. Herein, we examined the effects of overexpressing or knocking out NAMPT in adipocytes on metabolic dysfunction and interorgan communication in mice. We generated new adipocyte-specific NAMPT overexpressing( ANOV ) mice model. Male ANOV mice are protected from diet-induced metabolic dysfunction including adipose tissue inflammation, glucose intolerance, and insulin resistance. In contrast female ANOV mice were less protected from metabolic dysfunction, possibly due to higher endogenous expression of NAMPT in WT female mice. Livers of ANOV mice showed improved insulin signaling, increased NAD content, and reduced steatosis, suggesting that NAMPT regulates interorgan communication between adipocytes and hepatocytes. Extracellular vesicles (EV) isolated from ANOV mice enhanced insulin signaling in HepG2 cells and improved glucose tolerance in WT obese mice. In contrast, EV from ANKO mice suppressed HepG2 insulin signaling and inhibition of EV release improved glucose tolerance in ANKO female mice. Collectively, these data highlight a novel mechanism by which adipocyte NAD+ metabolism regulates systemic metabolic dysfunction via EVs.
    DOI:  https://doi.org/10.1101/2025.09.30.679563
  9. J Transl Med. 2025 Nov 18. 23(1): 1308
    Regulation of m6A methylation in the immune microenvironment in the development of diabetes mellitus.
    Haoyue Deng, Qiang Liu, Yanning Gong, Yue Qiu.
      Diabetes mellitus is a widespread metabolic disorder characterized by chronic hyperglycemia, driven primarily by insulin resistance and β-cell dysfunction. N6-methyladenosine (m6A), the most prevalent internal RNA modification in eukaryotes, has emerged as a critical regulator in diabetes pathogenesis. This review outlines how m6A methylation, mediated by writers (METTL3, METTL14), erasers (FTO, ALKBH5), and readers (YTHDFs, IGF2BPs), influences key diabetic processes including β-cell function, lipid metabolism, and insulin resistance. A key focus is on the role of m6A in modulating the immune microenvironment, such as by regulating macrophage polarization and T-cell activity, which contributes to inflammation and disease progression in both type 1 and type 2 diabetes. Furthermore, m6A dysregulation is implicated in multiple diabetic complications. Therapeutic agents, including existing drugs, natural extracts, and specific m6A inhibitors, can modulate m6A levels, highlighting its potential as a therapeutic target. This review synthesizes the evidence linking m6A to diabetes, with an emphasis on immunoregulation, and suggests that targeting m6A pathways offers promise for future treatments.
    Keywords:  Diabetes; FTO; Insulin resistance; m6A; Β-cell dysfunction
    DOI:  https://doi.org/10.1186/s12967-025-07331-3
  10. Cell Metab. 2025 Nov 18. pii: S1550-4131(25)00473-5. [Epub ahead of print]
    Gut microbiome-adipose crosstalk modulates soluble IL-6 receptor influencing exercise responsiveness in glycemic control and insulin sensitivity.
    Yao Wang, Jiaming Wu, Jianyu Yao, Jiarui Chen, Kenneth K Y Cheng, Melody Yuen-Man Ho, Chi Ho Lee, Karen Siu-Ling Lam, Michael Andrew Tse, Gianni Panagiotou, Aimin Xu.
      Exercise is an effective intervention for the prevention and management of diabetes, but the high interpersonal variability in response to exercise impedes its widespread implementation. Herein, we identify adipocyte-derived soluble interleukin-6 receptor (sIL-6R) as a key exerkine determining exercise efficacy in improving metabolic health. In individuals with obesity who underwent a 12-week exercise intervention, circulating sIL-6R level exhibits dichotomous changes between exercise responders (Rs) and non-responders (NRs), in close association with exercise-mediated alterations in insulin sensitivity and glycemic control. Mechanistically, elevated gut microbiome-mediated leucine in NR acts on white adipocytes to promote disintegrin and metalloproteinase 17 (ADAM17)-mediated sIL-6R production via the mammalian target of rapamycin (mTOR)-hypoxia-inducible factor 1α (HIF1α) pathway, which in turn impairs the metabolic benefits of exercise through interleukin (IL)-6 trans-signaling-induced adipose inflammation. Adipocyte-selective ablation of ADAM17 prevents the effects of fecal microbiota transplantation from NR on elevation of sIL-6R, thereby restoring the efficacy of exercise-shaped gut microbiome in counteracting glucose intolerance and insulin resistance in obese mice. Thus, therapeutic interventions targeting adipocyte-derived sIL-6R represent a promising strategy for maximizing exercise efficacy in personalized diabetes prevention.
    Keywords:  ADAM17; IL-6 signaling; adipokines; adipose inflammation; diabetes prevention; exercise interventions; exerkines; gut-adipose tissue crosstalk; insulin resistance; leucine
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.013
  11. iScience. 2025 Nov 21. 28(11): 113746
    Mitochondrial variation in Taiwan Biobank reveals ancestry structure and trait associations.
    Ting-Hsuan Chou, Pei-Miao Chien, Pin-Xuan Chen, Ni-Chung Lee, Hurng-Yi Wang, Yi-Cheng Chang, Chien-Yu Chen, Pei-Lung Chen, Jacob Shu-Jui Hsu.
      Mitochondrial DNA (mtDNA) variation contributes to human health, but its role in the Taiwanese population remains largely unexplored. Here, we comprehensively analyzed mtDNA variation in the Taiwan Biobank (TWB) by genotyping 1,492 individuals using whole-genome sequencing and imputing variants for 101,473 participants from microarray data. We identified 23 pathogenic mtDNA variants, with approximately 1 in 180 individuals carrying such variants. Analyses of mitochondrial genetic diversity revealed subtle differentiation among maternal ancestry groups. A mitochondrial genome-wide association study across 86 traits identified novel links between MT-ND2 variants and high myopia, as well as 14 variants associated with renal function biomarkers. Notably, renal-associated variants clustered into two groups: ancestral variants of macrohaplogroup M associated with reduced renal function and B4b sub-haplogroup variants linked to improved function. These findings highlight the value of population-specific mtDNA studies in advancing our understanding of mitochondrial genetics and health.
    Keywords:  Biological sciences; Genomic analysis; Genomics; Population
    DOI:  https://doi.org/10.1016/j.isci.2025.113746
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