bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–05–18
eight papers selected by
Rachel M. Handy, University of Guelph



  1. Nat Metab. 2025 May 13.
      Adipose tissue (AT) is a complex connective tissue with a high relative proportion of adipocytes, which are specialized cells with the ability to store lipids in large droplets. AT is found in multiple discrete depots throughout the body, where it serves as the primary repository for excess calories. In addition, AT has an important role in functions as diverse as insulation, immunity and regulation of metabolic homeostasis. The Human Cell Atlas Adipose Bionetwork was established to support the generation of single-cell atlases of human AT as well as the development of unified approaches and consensus for cell annotation. Here, we provide a first roadmap from this bionetwork, including our suggested cell annotations for humans and mice, with the aim of describing the state of the field and providing guidelines for the production, analysis, interpretation and presentation of AT single-cell data.
    DOI:  https://doi.org/10.1038/s42255-025-01296-9
  2. Mol Metab. 2025 May 12. pii: S2212-8778(25)00075-4. [Epub ahead of print] 102168
       OBJECTIVES: We previously identified tetraspanin 7 (Tspan7) as a candidate gene influencing body weight in an obesity-related gene screening study. However, the mechanisms underlying its involvement in body weight regulation remained unclear. This study aims to investigate the role of TSPAN7 from a metabolic perspective.
    METHODS: We utilized genetically modified mice, including adipose tissue-specific Tspan7-knockout and Tspan7-overexpressing models, as well as human adipose-derived stem cells with TSPAN7 knockdown and overexpression. Morphological, molecular, and omics analyses, including proteomics and transcriptomics, were performed to investigate TSPAN7 function. Physiological effects were assessed by measuring blood markers associated with lipid regulation under metabolic challenges, such as high-fat feeding and aging.
    RESULTS: We show that TSPAN7 is involved in regulating lipid droplet formation and stabilization. Tspan7-knockout mice exhibited an increased proportion of small-sized adipocytes and a reduced visceral-to-subcutaneous fat ratio. This shift in fat distribution was associated with improved insulin sensitivity and altered branched-chain amino acid metabolism, as evidenced by increased expression of the branched-chain α-keto acid dehydrogenase complex subunit B in Tspan7-modified mice. Mechanistically, TSPAN7 deficiency promoted subcutaneous fat expansion, alleviating metabolic stress on visceral fat, a major contributor to insulin resistance.
    CONCLUSIONS: TSPAN7 influences lipid metabolism by modulating adipose tissue remodeling, particularly under metabolic challenges, such as high-fat diet exposure and aging. Its modulation enhances subcutaneous fat storage capacity while mitigating visceral fat accumulation, leading to improved insulin sensitivity. These findings position TSPAN7 as a potential target for therapeutic interventions aimed at improving metabolic health and preventing obesity-related diseases.
    Keywords:  Fat distribution; Fat remodeling; Insulin resistance; Lipid droplet; Obesity; Tetraspanin7; Visceral-to-subcutaneous fat ratio
    DOI:  https://doi.org/10.1016/j.molmet.2025.102168
  3. Mol Metab. 2025 May 08. pii: S2212-8778(25)00068-7. [Epub ahead of print] 102161
      The cellular composition and functionality of adipose tissue are key determinants of metabolic diseases associated with adipose tissue dysregulation, such as obesity. We hypothesized that distinct subpopulations with unique gene expression profiles and functional characteristics exist within human adipocytes. Dedifferentiated adipocytes (DFAT), obtained by ceiling culture of human adipocytes, were analyzed using single-cell RNA sequencing (10x Genomics). Clustering analysis identified one subpopulation with a particular gene signature containing muscle cell genes. This subpopulation, named cluster 7 (C7), was isolated by FACS using two specific surface markers: cluster of differentiation 36 (CD36) and melanoma cell adhesion molecule (MCAM/CD146). Upon differentiation into adipocytes, the FACS-isolated CD36+/CD146+ cells (C7∗) showed an increased oxygen consumption rate compared to CD36-/CD146-cells (control cells) and non-sorted cells. Bulk RNA-sequencing revealed important pathways regulated in the differentiated C7∗ subpopulation that may contribute to its increased metabolic activity. Furthermore, the relative abundance of this specific cluster varied across eleven different human donors, demonstrating an inverse correlation between the proportion of C7∗ cells and the body mass index (BMI) of the respective donor. Importantly, a subset of genes regulated within this subpopulation also correlates with clinically relevant metabolic parameters, including weight, BMI, glycated hemoglobin, and plasma insulin, when analyzed alongside the gene expression of a large cohort of human subcutaneous adipose tissue (1759 donors). Our results not only characterize DFAT cells derived from human adipose tissue, but also identify a specific subpopulation with increased energy expenditure that may play a role in body weight control. Future efforts to identify possible therapeutic targets or to promote the enrichment or activation of these energy-burning cells in adipose tissue might be useful in the field of cardiometabolic diseases.
    Keywords:  Adipocytes; CD146; CD36; DFAT; Energy expenditure; Obesity
    DOI:  https://doi.org/10.1016/j.molmet.2025.102161
  4. Nat Commun. 2025 May 12. 16(1): 4374
      Alterations in mitochondrial metabolism in obesity may indicate disrupted communication between mitochondria and nucleus, and DNA methylation may influence this interplay. Here, we leverage data from the Finnish Twin Cohort study subcohort (n = 173; 86 full twin pairs, 1 singleton), including comprehensive measurements of obesity-related outcomes, mitochondrial DNA quantity and nuclear DNA methylation levels in adipose and muscle tissue, to identify one CpG at SH3BP4 significantly associated with mitochondrial DNA quantity in adipose tissue (FDR < 0.05). We also show that SH3BP4 methylation correlates with its gene expression. Additionally, we find that 14 out of the 35 obesity-related traits display significant associations with both SH3BP4 methylation and mitochondrial DNA quantity in adipose tissue. We use data from TwinsUK and the Scandinavian T2D-discordant monozygotic twin cohort, to validate the observed associations. Further analysis using ICE FALCON suggests that mitochondrial DNA quantity, insulin sensitivity and certain body fat measures are causal to SH3BP4 methylation. Examining mitochondrial DNA quantity and obesity-related traits suggests causation from mitochondrial DNA quantity to obesity, but unmeasured within-individual confounding cannot be ruled out. Our findings underscore the impact of mitochondrial DNA quantity on DNA methylation and expression of the SH3BP4 gene within adipose tissue, with potential implications for obesity.
    DOI:  https://doi.org/10.1038/s41467-025-59576-7
  5. Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2426179122
      Mitochondrial energy metabolism is vital for muscle function and is tightly controlled at the transcriptional level, both in the basal state and during adaptive muscle remodeling. The importance of the transcription factors estrogen-related receptors (ERRs) in controlling innate mitochondrial energetics has been recently demonstrated. However, whether different ERR isoforms display distinct functions in glycolytic versus oxidative myofibers is largely unknown. Moreover, their roles in regulating exercise-induced adaptive mitochondrial biogenesis remain unclear. Using muscle-specific single and combinatorial knockout mouse models, we have identified both cooperative and distinct roles of the ERR isoforms ERRα and ERRγ in regulating mitochondrial energy metabolism in different muscles. We demonstrate the essential roles of both these ERRs in mediating adaptive mitochondrial biogenesis in response to exercise training. We further show that PGC1α-induced mitochondrial biogenesis is completely abolished in primary myotubes with ERRα deletion but not ERRγ, highlighting distinct roles of these two isoforms in adaptive mitochondrial remodeling. Mechanistically, we find that both ERRs directly bind to the majority of mitochondrial energetic genes and control their expression, largely through collaborative binding to the same genomic loci. Collectively, our findings reveal critical and direct regulatory roles of ERRα and ERRγ in governing both innate and adaptive mitochondrial energetics in skeletal muscle.
    Keywords:  PGC1; energy metabolism; estrogen-related receptor; mitochondria; muscle
    DOI:  https://doi.org/10.1073/pnas.2426179122
  6. J Clin Endocrinol Metab. 2025 May 12. pii: dgaf280. [Epub ahead of print]
       BACKGROUND: Short-chain fatty acids, such as propionate, are produced from the fermentation of dietary fibre by gut microbiota and modulate adipose tissue metabolism to influence whole-body metabolic processes. Abdominal adipose tissue, critical in glucose and lipid homeostasis, is categorised into mesenteric, omental, and subcutaneous types based on its location. Adipose tissues display different metabolic phenotypes due to their distinct adipocyte lineages-white, brown, and beige. Recent evidence points to a significant impact of propionate on abdominal adipose tissue. Our study investigated the actions of propionate on the three types of human abdominal adipose tissue.
    METHODS: Adipose tissue from distinct depots (mesenteric, omental and subcutaneous) were collected from 40 patients who underwent open abdominal surgery for cholecystectomy or explorative laparotomy. Tissue explants and isolated adipocytes were treated with 1 mM propionate to assess adipose tissue browning and metabolic homeostatis.
    RESULTS: Propionate upregulated brown fat markers UCP1 and PGC1α in adipose tissue and mature adipocytes, particularly of mesenteric origin.Propionate exposure led to increased mitochondrial respiration and ATP production, primarily in mesenteric adipocytes, along with improved glucose uptake and reduced lipolysis and inflammation. In addition, propionate increased thermogenesis, glycolysis, and lipogenesis.
    CONCLUSION: The pronounced response of mesenteric adipose tissue to propionate underscores its potential as a therapeutic target for managing abdominal obesity and metabolic disorders.
    Keywords:  Adipose Tissue; Browning; Propionate; SCFA; Thermogenesis
    DOI:  https://doi.org/10.1210/clinem/dgaf280
  7. Cells. 2025 Apr 29. pii: 653. [Epub ahead of print]14(9):
      α-ketoglutarate dehydrogenase complex (KGDHc) is a crucial enzyme in the tricarboxylic acid (TCA) cycle that intersects monosaccharides, amino acids, and fatty acid catabolism with oxidative phosphorylation (OxPhos). A key feature of KGDHc is its ability to sense changes in the redox environment through the reversible oxidation of the vicinal lipoic acid thiols of its dihydrolipoamide succinyltransferase (DLST; E2) subunit, which controls its activity and, by extension, OxPhos. This characteristic inculcates KGDHc with redox regulatory properties for the modulation of metabolism and mediating of intra- and intercellular signals. The innate capacity of KGDHc to participate in the regulation of cell redox homeodynamics also occurs through the production of mitochondrial hydrogen peroxide (mtH2O2), which is generated by the dihydrolipoamide dehydrogenase (DLD; E3) downstream from the E2 subunit. Reversible covalent redox modification of the E2 subunit controls this mtH2O2 production by KGDHc, which not only protects from oxidative distress but also modulates oxidative eustress pathways. The importance of KGDHc in modulating redox homeodynamics is underscored by the pathogenesis of neurological and metabolic disorders that occur due to the hyper-generation of mtH2O2 by this enzyme complex. This also implies that the targeted redox modification of the E2 subunit could be a potential therapeutic strategy for limiting the oxidative distress triggered by KGDHc mtH2O2 hyper-generation. In this short article, I will discuss recent findings demonstrating KGDHc is a potent mtH2O2 source that can trigger the manifestation of several neurological and metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), inflammation, and cancer, and the targeted redox modification of the E2 subunit could alleviate these syndromes.
    Keywords:  KGDHc; NAFLD; hydrogen peroxide; metabolic diseases; mitochondria; oxidative distress; oxidative eustress; succinate
    DOI:  https://doi.org/10.3390/cells14090653
  8. J Nutr Biochem. 2025 May 09. pii: S0955-2863(25)00121-4. [Epub ahead of print] 109958
      Menopause induces physiological alterations predisposing women to the development of chronic diseases. The evaluation of postprandial responses allows for a comprehensive assessment of metabolism and biomarkers that may predispose to chronic disease risk. By applying a dietary challenge consisting of the ingestion of a liquid, energy-dense mixed meal, followed by blood sampling over a 6-hour period, we conducted a cross-sectional study to investigate the postprandial metabolism in postmenopausal women (PM) aged 50-70 years and women of reproductive age (RA) aged 20 and 40 years. PM body weight was only 10% higher than RA, but the first displayed twice as much (more than 20%) intrabdominal adipose tissue. PM also displayed elevated fasting and postprandial glycemia (∼20%) and lipidemia compared to RA. Differences were also observed in the postprandial levels of lactate. Both groups displayed a similar increase in white blood cell count during the challenge, despite large differences in peripheral blood mononuclear cells (PBMC) gene expression in both fasting and postprandial states, suggesting a pro-inflammatory state and HIF-α and glycolytic pathway activation in PM. Plasma levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) were increased in PM (37 and 52%, respectively). Postprandial plasma levels of incretins presented different kinetics to each group. Our findings reveal that PM display a pro-inflammatory signature and markers of metabolic deterioration after a 12-hour fasting and in the postprandial period when compared to RA.
    Keywords:  aging; immunometabolism; insulin resistance; menopause
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.109958