bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–10–26
eleven papers selected by
Rachel M. Handy, University of Guelph



  1. Diabetes. 2025 Oct 20. pii: db250222. [Epub ahead of print]
      Adipocyte size is linked to insulin resistance and the risk of developing type 2 diabetes. We aimed to generate a surrogate method to estimate adipocyte size by measuring adipose tissue gene expression using quantitative real-time PCR (qRT-PCR), which could be used alongside systemic measures of insulin sensitivity to predict type 2 diabetes risk. We examined the relationship of 40,591 genes with abdominal subcutaneous adipocyte size in 132 adults and validated the findings in additional cohorts with available transcriptomic and adipocyte size data. qRT-PCR analysis of gene expression in abdominal adipose tissue biopsies was used to develop a standardized adipocyte size estimate. This estimate was compared alongside systemic and adipose insulin sensitivity measures, including adipocyte lipogenesis, hyperinsulinemic-euglycemic clamp, adipose insulin resistance, and HOMA. Transcriptome-wide analyses found that UCHL1 gene expression strongly correlated with adipocyte size, independent of other genes and additional cofactors, such as insulin resistance (β-coefficient 0.32; P = 0.002). Using qRT-PCR, UCHL1 expression accurately estimated adipocyte size across a wide range of adipocyte volumes with high precision (receiver operating characteristic area under the curve 0.94) and showed strong correlations with all insulin sensitivity measures (adjusted r2 = 0.2-0.6; P < 0.0001). We scaled the measurement of UCHL1 expression to 25-mg adipose biopsies and provided a standard operating procedure for routinely estimating adipocyte size. In summary, we provide a simple, accurate, and accessible surrogate measure to estimate an individual's adipocyte size, which may be useful in clinical insulin resistance studies.
    ARTICLE HIGHLIGHTS: Adipocyte size is linked to insulin resistance and the risk of developing type 2 diabetes. A surrogate method was generated to estimate adipocyte size by measuring adipose tissue gene expression using quantitative real-time PCR. UCHL1 expression was found to correlate across a wide range of adipocyte cell volumes (38-1,420 pL) and to strongly and independently correlate with measured adipocyte volume when examined alongside measures for insulin resistance. Clinicians can use this method to estimate adipocyte size from an adipose tissue needle biopsy and routine quantitative real-time PCR measurement using the provided equation and methodological framework.
    DOI:  https://doi.org/10.2337/db25-0222
  2. J Appl Physiol (1985). 2025 Oct 20.
      Intermuscular adipose tissue (IMAT) is an anatomically distinct depot that is associated with metabolic dysfunction and aging. IMAT decreases with exercise in older adults with obesity, but less is known about how exercise influences IMAT in healthy, non-obese older adults in relation to insulin sensitivity. The purpose of this study was to determine if lower leg IMAT accumulates in healthy older adults in the absence of obesity, diabetes, or frailty and its relationship to insulin sensitivity. We also determined the influence of exercise training on lower leg IMAT. 29 young (25.0 ± 3.7 years) and 22 older (70.0 ± 4.0 years) adults underwent MRI-based measurements of lower leg IMAT and insulin sensitivity measurements by hyperinsulinemic euglycemic clamp before and after 12 weeks of exercise training. IMAT was higher in older compared to young adults (521 ± 217 mm3 vs 278 ± 131 mm3; p<0.0001). The glucose infusion rate (GIR) during hyperinsulinemia was similar in young and older adults (13.5 ± 2.9 mg/kg FFM/min vs 14.1 ± 4.2 mg/kg FFM/min; p=0.38), but negatively associated with IMAT (r=-0.43; p=0.002), particularly in older adults (r=-0.55; p=0.01). Exercise training reduced IMAT in young (p=0.04) but not older adults. GIR increased in response to exercise but dissociated from changes in IMAT. These data demonstrate that lower leg IMAT accumulated even in healthy aging, and although IMAT may have metabolic implications, the metabolic improvements with exercise training appear to be independent of lower leg IMAT in this population of older adults.
    Keywords:  Aging; exercise; glucose; intermuscular adipose; muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00719.2025
  3. Diabetol Metab Syndr. 2025 Oct 22. 17(1): 403
       BACKGROUND: Metabolic syndrome (MetS) is characterized by obesity, insulin resistance, and dyslipidemia with adipose tissue inflammation, yet its cellular heterogeneity and intercellular interactions remain poorly understood. We analyzed single-nucleus RNA sequencing data from subcutaneous adipose tissue of 84 individuals with MetS from the METSIM cohort, characterizing cell composition, inter-individual variation, adipocyte progenitor differentiation, and cell-cell communication networks.
    METHODS: We performed single-nucleus RNA sequencing on subcutaneous adipose tissue samples from 84 individuals with MetS. Clustering analysis was used to define cell types and subpopulations, inter-individual variation in cell composition was assessed, pseudotime trajectory analysis reconstructed adipocyte precursor differentiation pathways, and ligand-receptor interaction analysis mapped intercellular communication networks.
    RESULTS: We identified 12 distinct cell types in MetS adipose tissue and discovered two patient subgroups with differential enrichment of adipocytes/progenitors versus immune cells, suggesting subtypes of MetS with distinct adipose profiles. Pseudotime analysis revealed two adipocyte progenitor subpopulations with altered differentiation trajectories. Cell-cell communication analysis identified WNT signaling from progenitors to adipocytes as a potential differentiation driver, with extracellular matrix pathways mediating progenitor-adipocyte interactions.
    CONCLUSION: This comprehensive single-cell atlas of MetS adipose tissue reveals previously unrecognized cellular heterogeneity and differentiation dynamics, offering new insights into MetS pathogenesis and highlighting potential therapeutic targets.
    Keywords:  Adipose tissue; Cellular heterogeneity; Metabolic syndrome; Obesity
    DOI:  https://doi.org/10.1186/s13098-025-01975-3
  4. J Clin Endocrinol Metab. 2025 Oct 24. pii: dgaf586. [Epub ahead of print]
       BACKGROUND: Adiposomes carry bioactive lipids that shape systemic metabolism and vascular function. Building on our previous findings that obese adiposomes are ceramide/FFA-enriched and linked to dysfunction, we tested whether bariatric surgery remodels adiposome lipidomes and whether these shifts track with metabolic and vascular improvements.
    METHODS: Twenty-three obese individuals were assessed before and after bariatric surgery. Clinical evaluations included BMI, body composition, glycemic markers, inflammatory markers, and vascular function. Adipose tissue biopsies were collected, and adiposomes were isolated for non-targeted lipidomic analysis using mass spectrometry.
    RESULTS: Bariatric surgery induced significant reductions in BMI, visceral fat, HOMA-IR, inflammatory markers, and systolic blood pressure, alongside marked improvements in vascular function. Adiposome Lipidomics identified 550 species across 19 classes; 124 increased and 66 decreased post-surgery. Class-level shifts showed decreases in triglycerides, diglycerides, cholesteryl-esters, Phosphatidic-acids, fatty-acids, and acylcarnitines, with increases in phosphocholines, phosphoethanolamines, lysophosphatidylcholines, sphingomyelins, ultralong-chain Ceramides, and FAHFAs; these changes were larger in participants with ≥20% BMI reduction. Changes in 36 lipid species correlated with BMI change, e.g., TG 18:1/20:4/22:6 positively, whereas SM d40:1, SM d42:4, and PC 17:0/18:2 inversely. Improvements in nitric oxide, vascular reactivity, and adiponectin tracked with rises in ultralong-chain Cer/FAHFAs/phospholipids and declines in ACar/CE/DG/PA. Machine learning models predicted BMI from lipid features with >80% accuracy (R² > 0.90; MAE < 0.3), highlighting SM d40:1, SM d42:4, and FA 17:1 as top contributors. Pathway enrichment analysis linked these changes to sphingolipid signaling and glycerophospholipid metabolism.
    CONCLUSION: Bariatric surgery remodels adiposome lipids, and these shifts align with improvements in cardiometabolic risk markers.
    Keywords:  Adiposomes; Bariatric Surgery; Cardiometabolic risk; Extracellular vesicles; Lipidomics; Obesity
    DOI:  https://doi.org/10.1210/clinem/dgaf586
  5. Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2515947122
      Cullin Ring E3 Ligases (CRLs) belong to the largest family of multisubunit ubiquitin E3 ligases. A cullin serves as the scaffold protein that recruits E3 ligases and substrate receptors in a CRL complex, whose activity requires cullin neddylation, a posttranslational modification that can be pharmacologically targeted by neddylation inhibitors. Elevated neddylation activity has been observed in the liver and adipose tissue of obese mice, implicating a pathogenic link between altered CRL activity and the development of metabolic disorders. Emerging evidence has also shown that neddylation inhibitors possess antiobesity and hypoglycemic property. However, the roles of cullin proteins in regulating adipocyte biology are still incompletely defined. Here, we report that pan neddylation inhibitor TAS4464 treatment reversed obesity and adipose inflammation, resulting in improved hepatic steatosis and insulin sensitivity in obese mice. Among all mammalian cullin proteins that were targeted by TAS4464, we identified that cullin 3 (Cul3) was required for adipogenesis and adipocyte hypertrophy. A complete absence of Cul3 in adipocytes caused severely inhibited adipose expansion associated with ectopic fat accumulation in the liver and brown adipose tissue and insulin resistance, while adipocyte-specific Cul3 haploinsufficiency attenuated obesity and improved overall metabolic homeostasis, which recapitulated the metabolic benefits of TAS4464. Mechanistically, we found that Cul3 inhibition caused adipose nuclear factor erythroid 2-related factor 2 (NRF2) stabilization, which contributed to impaired adipogenesis by inhibiting lipogenesis. Together, these findings demonstrate that Cul3 is required during adipogenesis and acts as a downstream mediator of the antiobesity effect of pan neddylation inhibitors.
    Keywords:  adipogenesis; diabetes; insulin resistance; obesity
    DOI:  https://doi.org/10.1073/pnas.2515947122
  6. Diabetes. 2025 Nov 01. 74(11): 2044-2059
      Low birth weight (LBW) is a risk factor for type 2 diabetes (T2D). We hypothesized that 4 weeks of carbohydrate overfeeding (COF) with +25% energy would unmask key T2D perturbations among 22 nonobese LBW men, including five with screen-detected metabolic dysfunction-associated steatotic liver disease (MASLD), compared with 21 healthy control participants with normal birth weight (NBW). Body weight, lean and fat mass, and hepatic fat content increased to the same extent in both groups during COF, whereas fasting glucose and insulin resistance increased significantly more in LBW compared with NBW participants. The differential COF responses were most pronounced in LBW participants without MASLD, including increased resting energy expenditure. Plasma adiponectin was lower, whereas fibroblast growth factor 21 levels increased more during COF in LBW participants. Subcutaneous adipose tissue (SAT) density was lower in LBW participants and decreased during COF in both groups. Serum alanine, phosphatidylcholines, and triglycerides increased significantly more in LBW participants during COF. Multiomics analysis of SAT RNA sequencing, serum lipidomics, and metabolomics uncovered impaired peroxisome proliferator-activated receptor signaling as well as aberrant collagen and extracellular matrix regulation in LBW participants. The results document differential and MASLD-independent metabolic perturbations in LBW participants during COF.
    ARTICLE HIGHLIGHTS: Individuals with low birth weight (LBW) are at increased risk of type 2 diabetes. Four weeks of carbohydrate overfeeding (COF) was associated with differential elevations in fasting glucose, lipids, alanine, insulin resistance, and resting energy expenditure in LBW participants versus control participants. Multiomics analyses indicated reduced peroxisome proliferator-activated receptor signaling, as well as differential expression of genes involved in collagen and extracellular matrix metabolism in LBW participants during COF. Interestingly, the COF perturbations in LBW participants became more pronounced when excluding five LBW men with screen-detected metabolic dysfunction-associated steatotic liver disease. The findings support the notion of unhealthy subcutaneous adipose tissue expandability potentially underlying a reduced metabolic buffering capacity in nonobese LBW men.
    DOI:  https://doi.org/10.2337/db25-0307
  7. ACS Appl Mater Interfaces. 2025 Oct 23.
      Obesity remains a growing and global public health burden across a broad spectrum of metabolic, systemic, and neurodegenerative diseases. Previously considered merely a fat storage depot, adipose tissue is now recognized as an active endocrine organ crucial for the metabolic and systemic regulation of local and distant organs. A burgeoning line of investigation centers on adipose-derived extracellular vesicles (ADEVs) and their pivotal role in obesity-associated pathobiology. However, robust methodologies for specifically isolating and characterizing human ADEVs are lacking. To bridge this gap, we developed a robust multiparametric framework incorporating bulk and single EV characterization, proteomics, and mRNA phenotyping. EVs from matched human visceral adipose tissue, mature adipocyte-conditioned media, and plasma collected from the same bariatric surgical patients were analyzed and subjected to bottom-up proteomics analysis. This framework integrates bulk EV proteomics for cell-specific marker identification and subsequent single EV interrogation with single-particle interferometric reflectance imaging (SP-IRIS) and total internal reflection fluorescence (TIRF) microscopy. Our proteomics analysis revealed 76 unique proteins from adipose tissue-derived EVs (ATEVs), 512 unique proteins from adipocyte EVs (aEVs), and 1003 shared proteins. Prominent pathways enriched in ATEVs included lipid metabolism, extracellular matrix organization, and immune modulation, while aEVs were enriched in chromatin remodeling, oxidative stress responses, and metabolic regulation pathways. Notably, we identified obesity-associated and adipose-specific proteins, such as TMEM120A and SACM1L, highly enriched in ATEVs, and histone variants, including MACROH2A1, H3-3A, H2AC20, H2BC12, and H3-7, uniquely upregulated in aEVs. Additionally, classical adipose-associated proteins such as adiponectin and perilipin were highly enriched in ADEVs and were confirmed in circulating plasma EVs. Colocalization of key EV and adipocyte markers, including CD63 and PPARG, was validated in circulating plasma EVs. In summary, our study paves the way toward a tissue and cell-specific, multiparametric framework for an 'adiposity EV signature' in obesity-driven diseases.
    Keywords:  adipocyte-derived EVs; adipose tissue-derived EVs; exosomes; extracellular vesicles; obesity
    DOI:  https://doi.org/10.1021/acsami.5c12767
  8. Cell Metab. 2025 Oct 22. pii: S1550-4131(25)00397-3. [Epub ahead of print]
      Adipocytes as vital energy reservoirs respond to systemic metabolic demands by storing or releasing lipids. Whether they can promote tissue regeneration through local metabolic communication remains unclear. We found that after skin injury, macrophages quickly infiltrate dermal adipose tissue, where they promote free fatty acid release from adipocytes via serum amyloid A3-dependent lipolysis, which, in turn, promotes hair regrowth. Epithelial hair follicle stem cells (eHFSCs) absorb the released monounsaturated fatty acids via fatty acid translocase CD36 and activate the transcriptional coactivator Pgc1-α. Downstream of Pgc1-α, increased fatty acid oxidation and mitochondrial biogenesis enhance energy production, enabling eHFSCs to exit quiescence. Topical treatment of monounsaturated fatty acids suffices to promote hair growth by activating eHFSCs. Our findings demonstrate a macrophage-to-adipocyte-to-hair follicle axis that promotes tissue-level regeneration via short-range metabolic signaling through free fatty acids. Analogous regeneration-facilitating mechanisms elicited by injury-induced panniculitis may operate in other adipose-rich organs.
    Keywords:  adipocyte; fatty acid oxidation; hair follicle; inflammation; lipolysis; macrophage; mitochondrial biogenesis; panniculitis; serum amyloid A3; tissue regeneration
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.012
  9. Commun Med (Lond). 2025 Oct 23. 5(1): 434
       BACKGROUND: Bariatric surgery enhances glucose metabolism, yet the detailed postprandial joint glucose and insulin responses, variability in individual outcomes, and differences in surgical approaches remain poorly understood.
    METHODS: We used hierarchical multi-output Gaussian process (HMOGP) regression to reveal clinically relevant patterns between persons undergoing two types of bariatric surgery by modeling the individual postprandial glucose and insulin responses and estimating the average response curves from individual data. 44 participants with obesity underwent either Roux-en-Y gastric bypass (RYGB; n = 24) or One-Anastomosis gastric bypass (OAGB; n = 20) surgery. The participants were followed up at the 6th and 12th months after the operation, during which they underwent an oral glucose tolerance test (OGTT) and a mixed meal test (MMT).
    RESULTS: A marked reduction in glycemia, an earlier glucose peak, and an increase and sharpening in the postprandial glucose and insulin responses are evident in both metabolic tests post-operation. MMT results in higher postprandial glucose and insulin peaks compared with OGTT. Higher glucose and insulin responses are observed after RYGB compared with OAGB, suggesting differences between the procedures that may influence the clinical practice.
    CONCLUSIONS: Computational modeling with HMOGP regression can thus be used to, in detail, predict the combined responses of patient cohorts to ingested glucose or a mixed meal and help in assessing individual metabolic improvement after weight loss. This can lead to new knowledge in personalized metabolic interventions.
    DOI:  https://doi.org/10.1038/s43856-025-01155-4
  10. Cell Metab. 2025 Oct 23. pii: S1550-4131(25)00433-4. [Epub ahead of print]
      In adipocytes, hormone-sensitive lipase (HSL) plays a key role in hydrolyzing triacylglycerols that are stored in lipid droplets. Contrary to the expected phenotype, HSL-deficient mice and humans exhibit lipodystrophy. Here, we show that HSL is also present in the adipocyte nucleus. Mouse models with different HSL subcellular localizations reveal that nuclear HSL is essential for the maintenance of adipose tissue. Gene silencing in human adipocytes shows that HSL, independently of its enzymatic activity, exerts opposing effects on mitochondrial oxidative phosphorylation and the extracellular matrix. Mechanistically, we found that HSL accumulates in the nucleus by interacting with the transforming growth factor β (TGF-β) signaling mediator, mothers against decapentaplegic homolog 3 (SMAD3). Conversely, HSL phosphorylation induces nuclear export. In vivo, HSL accumulates in the nucleus of adipocytes during high-fat feeding with the converse effect during fasting. Together, our data show that as both a cytosolic enzyme and a nuclear factor, HSL plays a pivotal role in adipocyte biology and adipose tissue maintenance.
    Keywords:  TGF-β signaling; adipocyte; adipose tissue; cell nucleus; extracellular matrix; hormone-sensitive lipase; lipodystrophy; mitochondrial oxidative phosphorylation; obesity; protein-protein interaction
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.014
  11. Aging Cell. 2025 Oct 21. e70278
      Aging and obesity are associated with pro-inflammatory changes in adipose tissue. Overlapping mechanisms, such as the infiltration of inflammatory macrophages and T cells into visceral adipose tissue, have been implicated in contributing to inflammation. However, a comparative analysis of both states is needed to identify distinct regulatory targets. Here, we performed single-cell RNA sequencing of stromal vascular fractions (SVF) isolated from gonadal white adipose tissue (gWAT) of young mice fed either a normal or a high-fat diet, and aged mice fed a normal diet. Our analysis revealed that physiological aging, compared to high-fat diet-induced obesity, was associated with an accumulation of phenotypically distinct CD8 T cells resembling virtual memory (VM) CD8 T cells. These cells expressed high levels of Cd44, Sell, Il7r, Il2rb, lacked Itga4, and exhibited elevated Fcgr2b expression which was associated with pseudotime differentiation trajectories. Flow cytometry confirmed an age-associated increase in Fcgr2b + CD49d- VM-like CD8 T cells in gWAT. Notably, these Fcgr2b-expressing cells exhibited a cytotoxic profile and expressed granzyme M. Functional analysis using recombinant granzyme M revealed its potential in inducing inflammation in mouse fibroblasts and macrophages. Together, our study has identified Fcgr2b + CD49d- VM-like CD8 T cells in the adipose tissue of aged mice with regulatory, cytotoxic, and inflammatory potential.
    Keywords:  CD8 T cells; adipose tissue; aging; memory T cells; obesity; single‐cell analysis
    DOI:  https://doi.org/10.1111/acel.70278