bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–11–02
six papers selected by
Rachel M. Handy, University of Guelph
  1. Stem Cell Secretome Treatment Reduces Adiposity and Improves Glucose Handling During Obesity and Weight Loss in Mice.
  2. Secretory kinase FAM20C triggers adipocyte dysfunction inciting insulin resistance and inflammation in obesity.
  3. Adipose Triglyceride Lipase Knockout Increases Anticontractile Effects of Perivascular Adipose Tissue.
  4. A Very-Low Energy Fast Involves Increased Adipose Inflammatory Gene Expression: A 6-Day Feeding Trial (FASTOMICS-6).
  5. Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ.
  6. Aerobic exercise training improves blood glucose homeostasis in healthy older adults.
  1. Obesity (Silver Spring). 2025 Oct 27.
    Stem Cell Secretome Treatment Reduces Adiposity and Improves Glucose Handling During Obesity and Weight Loss in Mice.
    Zachary J Fennel, Anu S Kurian, Paul-Emile Bourrant, Chad M Skiles, Robert J Castro, Elena M Yee, Scott A Greilach, Hans S Keirstead, Gabriel Nistor, Nicole C Berchtold, Thomas E Lane, Micah J Drummond.
       OBJECTIVE: In this study, we investigated the effects of a stem cell-derived secretome product on adiposity and tissue quality and insulin and glucose levels in obese mice and those undergoing dietary weight loss.
    METHODS: Following 16 weeks of high fat diet mice received acute (4 weeks) biweekly intramuscular injections with vehicle or secretome while remaining on a high fat diet (HFD vs. HFD-S) or during weight loss upon return to a normal chow diet (HFD/WL vs. HFD/WL-S).
    RESULTS: After 4 weeks of treatment, HFD-S mice had greater lean mass (vs HFD), muscle weights, and quadriceps myofibrillar size and improved muscle quality (capillary density and fibrosis). HFD/WL-S mice had accelerated whole-body fat loss and improved glucose handling, fasting insulin levels, and HOMA-IR. In both secretome-treated groups (HFD-S and HFD/WL-S), liver steatosis and fibrosis were improved and similar to chow controls.
    CONCLUSIONS: Together, these results support that a stem cell secretome treatment may be useful to improve tissue quality and metabolic health during obesity and weight loss.
    Keywords:  metabolism; obesity; stem cells; weight loss
    DOI:  https://doi.org/10.1002/oby.70068
  2. J Clin Invest. 2025 Oct 28. pii: e191075. [Epub ahead of print]
    Secretory kinase FAM20C triggers adipocyte dysfunction inciting insulin resistance and inflammation in obesity.
    Ankit Gilani, Benjamin D Stein, Anne Hoffmann, Renan Pereira de Lima, Elizabeth E Ha, Edwin A Homan, Lunkun Ma, Alfonso Rubio-Navarro, Tint Tha Ra Wun, Gabriel Jose Ayala Carrascal, Bhavneet Bhinder, Adhideb Ghosh, Falko J Noé, Olivier Elemento, Christian Wolfrum, Matthias Blüher, James C Lo.
      Obesity is a major driver of type 2 diabetes (T2D) and related metabolic disorders, characterized by chronic inflammation and adipocyte dysfunction. However, the molecular triggers initiating these processes remain poorly understood. We identify FAM20C, a serine/threonine kinase, as an early obesity-induced mediator of adipocyte dysfunction. Fam20c expression is substantially upregulated in adipocytes in response to obesity, correlating with a proinflammatory transcriptional signature. Forced expression of Fam20c in adipocytes promotes robust upregulation of proinflammatory cytokines and induces insulin resistance that is dependent on its kinase activity. Conversely, deletion of adipocyte Fam20c after established obesity and hyperglycemia improves glucose tolerance, augments insulin sensitivity, and reduces visceral adiposity, without altering body weight. Phosphoproteomic studies reveal that FAM20C regulates phosphorylation of intracellular and secreted proteins, modulating pathways critical to inflammation, metabolism, and extracellular matrix remodeling. We identify FAM20C-dependent substrates, such as CNPY4, whose phosphorylation contributes to proinflammatory adipocyte signaling. Of translational relevance, we show that in humans visceral adipose FAM20C expression positively correlates with insulin resistance. Our findings establish FAM20C as an early regulator of obesity-induced adipocyte dysfunction and systemic metabolic impairment. Our studies provide proof of concept that inhibition of FAM20C may serve as a potential therapy for T2D by restoring adipocyte health.
    Keywords:  Adipose tissue; Cell biology; Diabetes; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI191075
  3. Arterioscler Thromb Vasc Biol. 2025 Oct 30.
    Adipose Triglyceride Lipase Knockout Increases Anticontractile Effects of Perivascular Adipose Tissue.
    Astrid Schrammel, Gerald Wölkart, Elisabeth Ableitner, Martina Derler, Isabella Potoschnig, Gabriele Schoiswohl, Guenter Haemmerle, Christian Wolfrum, Erin E Kershaw, Sophie Theresa Schmid, Mahmoud Abdellatif, Simon Sedej, Rudolf Zechner, Martina Schweiger, Bernd Mayer, Marion Mussbacher.
       BACKGROUND: Perivascular adipose tissue (PVAT) fine-tunes blood vessel contractility and vascular homeostasis. During obesity and atherosclerosis, PVAT becomes dysfunctional and loses its anticontractile potential. Previously, we reported that global knockout of ATGL (adipose triglyceride lipase), the major enzyme responsible for the breakdown of triglycerides, has the potential to modify PVAT functions. To address the causal relationship between PVAT lipolysis and blood vessel contractility, we analyzed ex vivo vasomotor function of mice with tissue-specific rescue/overexpression or knockout of ATGL in adipose tissue.
    METHODS: To generate mice lacking ATGL in all tissues except for adipose tissue (ATGL knockout with adipocyte-specific expression of ATGL [A+/AKO]), we crossed adipocyte ATGL-rescued (A+) mice with ATGL-deficient (ATGL knockout [AKO]) mice. Body weight, plasma levels of fatty acids, and blood glucose were compared between A+/AKO and AKO mice. Ex vivo vasoreactivity studies were performed in the absence and presence of PVAT to test for acute and chronic effects of PVAT on vascular function.
    RESULTS: Adipocyte-rescued AKO mice (A+/AKO) had significantly less amounts of PVAT than AKO controls while displaying moderate ATGL expression. A+/AKO aortas exhibited decreased anticontractile effects of PVAT compared with AKO aortas. This effect on contractile function was observed in an agonist-specific manner without affecting smooth muscle cell function or endothelium-dependent relaxation. Assessment of cardiac function using the Langendorff setup revealed that adipocyte ATGL selectively modulated vascular contractility without affecting systolic or diastolic performance. Studies using mice that express ATGL solely in cardiac muscle and adipocyte-specific ATGL knockout mice verified our findings in A+/AKO mice, revealing acute and chronic effects of adipocyte lipolysis on vasoreactivity.
    CONCLUSIONS: We provide the first evidence that changes in adipocyte lipolysis have the potential to regulate blood vessel contractility. Ablation of ATGL in adipocytes decreases vascular contractility and, thus, has the potential to prevent PVAT dysfunction in obesity and atherosclerosis.
    Keywords:  cardiovascular diseases; endothelial cells; glycerol; myocytes, cardiac; reactive oxygen species
    DOI:  https://doi.org/10.1161/ATVBAHA.125.322902
  4. J Clin Endocrinol Metab. 2025 Oct 28. pii: dgaf570. [Epub ahead of print]
    A Very-Low Energy Fast Involves Increased Adipose Inflammatory Gene Expression: A 6-Day Feeding Trial (FASTOMICS-6).
    Marianne Bråtveit, Pouda P Strømland, Johnny Laupsa-Borge, Lillian Skumsnes, Vigdis H Dagsland, Silje Kvistad, Elinor C Vogt, Adrian McCann, Håvard L Thorsen, Andreas P Diamantopoulos, Bjørn Gunnar Nedrebø, Gunnar Mellgren, Simon N Dankel.
       BACKGROUND: Fasting and ketogenic diets may have health benefits, but we lack a deeper understanding of tissue mechanisms and associated metabolome changes, particularly in humans.
    OBJECTIVE: Determine changes in subcutaneous adipose tissue (SAT) gene expression, plasma metabolomics and circulating serum markers after a 6-day very-low-energy fast.
    METHODS: 13 patients with obesity (mean BMI = 41.6) underwent a week-long in-hospital feeding study (600 kcal/day). Body composition was assessed by bioimpedance. Blood and SAT were collected on day 1 and 7 for metabolomics (GC-MS/MS) and transcriptomics (RNA-sequencing). Biological pathways were inferred from affected gene sets (GSEA) and gene networks that correlated with plasma metabolites (WGCNA).
    RESULTS: Relative mean change (95% CI) in fat mass and fat-free mass was -2.07% (-2.93, -1.20) and -4.42% (-5.53, -3.28), respectively. Marked significant changes (relative mean change (95% CI)) were observed in total ketone bodies (acetoacetate + β-hydroxybutyrate) (+615% (366, 999)), fasting insulin (-41.2% (-53.1, -26.4)) and HOMA2-IR (-31.8% (-41.4, -20.6)), as well as α-hydroxybutyrate (+103% (69.9, 142)) and the advanced glycation end-products (AGEs) Carboxyethyl-Lysine (-46.0% (-53.6, -37.2)) and Carboxymethyl-Lysine (-50.9% (-59.8, -40.1)). GSEA indicated upregulated inflammatory responses, and downregulated oxidative phosphorylation, adipogenesis, fatty acid metabolism and mTORC1 signaling (p<0.01) in SAT.
    CONCLUSION: After a 6-day very-low energy fast, adipose inflammatory gene expression increased concomitant with decreased plasma AGEs and improved insulin sensitivity. These data suggest a role for inflammatory and autophagy-associated pathways in the metabolic adaptation to a ketogenic very-low energy fast.
    Keywords:  Fasting; adipose tissue; calorie restriction; gene expression; metabolomics; obesity
    DOI:  https://doi.org/10.1210/clinem/dgaf570
  5. Mol Metab. 2025 Oct 29. pii: S2212-8778(25)00184-X. [Epub ahead of print] 102277
    Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ.
    Olivia Sveidahl Johansen, Rebecca L McIntyre, Janane F Rahbani, Qiaoqiao Zhang, Charlotte Scholtes, Damien Marc Lagarde, Cyrielle Billon, Isabelle Côté, Maria Delgado-Martin, David Tandio, Astrid Linde Basse, Elodie Eury, Anastasia Kralli, Thomas P Burris, Vincent Giguère, Lawrence Kazak, Zachary Gerhart-Hines.
       OBJECTIVES: Despite transformative advances in obesity pharmacotherapy, safely increasing energy expenditure remains a key unmet need. Exploiting thermogenic adipocytes represents a promising target given their capacity for significant catabolic activity. We previously showed that G protein-coupled receptor 3 (GPR3) can drive energy expenditure in brown and white mouse and human adipocytes. GPR3 is a unique GPCR because it displays high intrinsic activity and leads to constitutive cAMP signaling upon reaching the cell surface. Therefore, the transcriptional induction of GPR3 is analogous to ligand-binding activation of most GPCRs. Gpr3 expression is physiologically induced in thermogenic adipocytes by cold exposure, and mimicking this event through overexpression in mice is fully sufficient to increase energy expenditure and counteract metabolic disease. Yet the factors mediating physiological Gpr3 expression remain unknown.
    METHODS: Here, we apply ATAC-Seq to identify cold-induced promoter elements of Gpr3. We uncover a role for the estrogen-related receptors, ERRα and ERRγ, in the physiological transcriptional control of Gpr3 using adipose-specific double knock-out mice with and without adeno-associated virus (AAV)-mediated rescue.
    RESULTS: We show that ERRα directly binds the cold-induced promoter element of Gpr3 and that ERRα, ERRβ, and ERRγ each activate the Gpr3 promoter in vitro when co-transfected with PGC-1α. Adipocyte ERRα and ERRγ are required for the in vivo transcriptional induction of Gpr3 during cold exposure. Importantly, deficient Gpr3 cold-inducibility in adipose-specific ERRα and ERRγ KO mice is fully rescued by delivery of AAVs re-expressing either ERRα or ERRγ directly into brown adipose tissue.
    CONCLUSIONS: ERRα and ERRγ are critical regulators of cold-induced transcription of Gpr3 and represent a targetable strategy for pharmacologically unlocking GPR3-induced energy expenditure.
    Keywords:  ERRα; ERRγ; G protein-coupled receptors; GPR3; brown adipose tissue; thermogenesis; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.molmet.2025.102277
  6. Exp Gerontol. 2025 Oct 28. pii: S0531-5565(25)00269-4. [Epub ahead of print] 112940
    Aerobic exercise training improves blood glucose homeostasis in healthy older adults.
    Alejandra P Monsegue, Milan W Betz, Hasibe Aydeniz, Wendy E Sluijsmans, Luc J C van Loon, Tim Snijders, Lex B Verdijk.
      The present study assessed the effects of aerobic exercise training (AER) on blood glucose regulation in healthy older adults, and whether these effects depend on baseline glucose regulation. Thirty-four healthy older adults (71 ± 4 y) were randomized to perform 8 weeks of AER (n = 17) or no exercise (CON, n = 17). A five-point oral glucose tolerance test was performed at baseline and post-intervention to assess plasma glucose and insulin concentrations. Glucose regulation was assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), Hepatic Insulin Resistance Index (HIRI), Muscle Insulin Sensitivity Index (MISI), and Matsuda index. Two-factor repeated measures ANOVAs were performed on the full cohort and on a subgroup (CON: n = 10, AER: n = 9) with Matsuda index ≤5. Full Cohort Analyses: a significant interaction effect (P < 0.05) was observed only for HIRI (P = 0.025), which worsened in CON (+151 ± 232, P = 0.016) but not AER (-32 ± 221, P = 0.557). Subgroup Analyses: significant interaction effects were observed for hepatic glucose regulation (P ≤ 0.013), which worsened in CON (HOMA-IR: +0.5 ± 0.6, P = 0.085; HIRI: +249 ± 253, P = 0.006), but tended to improve in AER (HOMA-IR: -0.6 ± 1.2, P = 0.051; HIRI: -133 ± 241, P = 0.125). A significant interaction effect was observed for Matsuda index (P = 0.004), which increased in AER (from 3.2 ± 1.1 to 4.8 ± 2.1, P = 0.002), but remained unchanged in CON (from 3.8 ± 0.9 to 3.5 ± 1.4, P = 0.401). A trend toward an interaction effect was noted for MISI (AER: from 0.12 ± 0.07 to 0.19 ± 0.16; CON: from 0.18 ± 0.11 to 0.16 ± 0.06, P = 0.082). Aerobic exercise training improves blood glucose regulation in healthy older adults, with greater impact in those with a more compromised blood glucose regulation (based on Matsuda index≤5).
    Keywords:  Endurance exercise; Glucose regulation; HIRI; HOMA-IR; MISI; Matsuda index
    DOI:  https://doi.org/10.1016/j.exger.2025.112940
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