bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–07–13
eleven papers selected by
Rachel M. Handy, University of Guelph
  1. CagriSema drives weight loss in rats by reducing energy intake and preserving energy expenditure.
  2. HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.
  3. High-fat diet ablates an insulin-responsive pool of GLUT4 glucose transporters in skeletal muscle.
  4. Selective remodelling of the adipose niche in obesity and weight loss.
  5. Adipocyte-specific modulation of 11β-HSD enzymes for the treatment of obesity in male mice.
  6. Glucagon-like peptide-1 is involved in fasting and postprandial blood flow regulation of subcutaneous adipose tissue.
  7. Caloric Restriction Promotes Resolution of Atherosclerosis in Obese Mice, while Weight Regain Accelerates its Progression.
  8. Lipidomic Signatures of Insulin Resistance Identified From Hyperinsulinemic-Euglycemic Clamp Studies in Asian Men.
  9. Hsp47 drives obesity-associated breast cancer progression by enhancing asporin deposition in adipose tissue.
  10. ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
  11. Morning Elevation in Insulin Enhances Afternoon Postprandial Insulin Action and Glucose Effectiveness.
  1. Nat Metab. 2025 Jul 08.
    CagriSema drives weight loss in rats by reducing energy intake and preserving energy expenditure.
    Julie Mie Jacobsen, Jens Frey Halling, Ida Blom, Jaime Moreno Martinez, Bjørn Hald, Kent Pedersen, Johannes Josef Fels, Søren Snitker, Anna Secher, Sofia Lundh, Carel W le Roux, Kirsten Raun, Marc L Reitman, Rune Ehrenreich Kuhre.
      CagriSema is a combination of amylin (cagrilintide) and glucagon-like peptide-1 (semaglutide) analogues being developed for weight management. Here, we show that CagriSema blunts metabolic adaptation in rats. Quantifying CagriSema's action on energy intake and expenditure in rats we observe 12% weight loss with a 39% reduction in food intake. By contrast, pair-feeding causes less-pronounced weight loss, while weight matching requires a 51% decrease in food intake. Therefore, approximately one-third of CagriSema's weight loss efficacy arises from an effect on energy expenditure, the blunting of metabolic adaptation, which contributes to the successful treatment of obesity.
    DOI:  https://doi.org/10.1038/s42255-025-01324-8
  2. Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2504080122
    HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.
    Amy M Ehrlich, Kirstin A MacGregor, Stephen P Ashcroft, Lewin Small, Ali Altıntaş, Alexander V Chibalin, Matthias Anagho-Mattanovich, Ben Stocks, Thomas Moritz, Jonas T Treebak, Juleen R Zierath.
      The regulation of metabolism in peripheral tissues is intricately linked to circadian rhythms, with hypoxia-inducible factor-1α (HIF1α) implicated in modulating time-of-day-specific exercise responses. To investigate this relationship, we generated a skeletal muscle-specific HIF1α knockout (KO) mouse model and performed extensive metabolic phenotyping and transcriptomic profiling under both basal conditions and following acute exercise during early rest (ZT3) and active (ZT15) phases. Our findings reveal that HIF1α drives a more robust transcriptional and glycolytic response to exercise at ZT3, promoting glucose oxidation and mannose-6-phosphate production while potentially sparing fatty acid oxidation. In the absence of HIF1α, skeletal muscle metabolism shifts toward oxidative pathways at ZT3, with notable alterations in glucose fate. These results establish HIF1α as an important regulator of time-of-day-specific metabolic adaptations, integrating circadian and energetic signals to optimize substrate utilization. This work highlights the broader significance of HIF1α in coordinating circadian influences on metabolic health and exercise performance.
    Keywords:  circadian; energy metabolism; exercise; metabolism; transcription factor
    DOI:  https://doi.org/10.1073/pnas.2504080122
  3. bioRxiv. 2025 Jul 03. pii: 2025.06.29.662135. [Epub ahead of print]
    High-fat diet ablates an insulin-responsive pool of GLUT4 glucose transporters in skeletal muscle.
    Youjia Hu, Stacey N Brown, Ali Nasiri, Don T Li, Haiyan Wang, Gregory D Cartee, Gerald I Shulman, Jonathan S Bogan.
      To stimulate glucose uptake in muscle, insulin mobilizes GLUT4 glucose transporters to the cell surface. During fasting, GLUT4 and the transmembrane aminopeptidase IRAP are trapped in intracellular, insulin-responsive vesicles bound by TUG, AS160, and Usp25m proteins. Here we show that Usp25m, a protease, is required for the bulk of insulin-stimulated TUG cleavage and consequent vesicle mobilization and glucose uptake. Efficient TUG cleavage also requires AS160. In mice with diet-induced insulin resistance, Usp25m abundance is reduced, IRAP is mislocalized during fasting, and TUG cleavage is impaired; effects of Usp25m and TUG deletion to alter insulin-stimulated and fasting glucose uptake, respectively, are ablated. We conclude that skeletal muscle insulin resistance results in part from altered membrane trafficking of GLUT4 and IRAP during fasting. This alteration depletes the pool of insulin-responsive vesicles marked by TUG and Usp25m. Mistargeting of GLUT4 and IRAP may contribute to distinct aspects of the metabolic syndrome in humans.
    DOI:  https://doi.org/10.1101/2025.06.29.662135
  4. Nature. 2025 Jul 09.
    Selective remodelling of the adipose niche in obesity and weight loss.
    Antonio M A Miranda, Liam McAllan, Guianfranco Mazzei, Ivan Andrew, Iona Davies, Meryem Ertugrul, Julia Kenkre, Hiromi Kudo, Joana Carrelha, Bhavik Patel, Sophie Newton, Weihua Zhang, Alice Pollard, Amy Cross, Oliver McCallion, Mikyung Jang, Ka Lok Choi, Scarlett Brown, Yasmin Rasool, Marco Adamo, Mohamed Elkalaawy, Andrew Jenkinson, Borzoueh Mohammadi, Majid Hashemi, Robert Goldin, Laurence Game, Joanna Hester, Fadi Issa, Dylan G Ryan, Patricia Ortega, Ahmed R Ahmed, Rachel L Batterham, John C Chambers, Jaspal S Kooner, Damir Baranasic, Michela Noseda, Tricia Tan, William R Scott.
      Weight loss significantly improves metabolic and cardiovascular health in people with obesity1-3. The remodelling of adipose tissue (AT) is central to these varied and important clinical effects4. However, surprisingly little is known about the underlying mechanisms, presenting a barrier to treatment advances. Here we report a spatially resolved single-nucleus atlas (comprising 171,247 cells from 70 people) investigating the cell types, molecular events and regulatory factors that reshape human AT, and thus metabolic health, in obesity and therapeutic weight loss. We discover selective vulnerability to senescence in metabolic, precursor and vascular cells and reveal that senescence is potently reversed by weight loss. We define gene regulatory mechanisms and tissue signals that may drive a degenerative cycle of senescence, tissue injury and metabolic dysfunction. We find that weight loss reduces adipocyte hypertrophy and biomechanical constraint pathways, activating global metabolic flux and bioenergetic substrate cycles that may mediate systemic improvements in metabolic health. In the immune compartment, we demonstrate that weight loss represses obesity-induced macrophage infiltration but does not completely reverse activation, leaving these cells primed to trigger potential weight regain and worsen metabolic dysfunction. Throughout, we map cells to tissue niches to understand the collective determinants of tissue injury and recovery. Overall, our complementary single-nucleus and spatial datasets offer unprecedented insights into the basis of obese AT dysfunction and its reversal by weight loss and are a key resource for mechanistic and therapeutic exploration.
    DOI:  https://doi.org/10.1038/s41586-025-09233-2
  5. Am J Physiol Cell Physiol. 2025 Jul 11.
    Adipocyte-specific modulation of 11β-HSD enzymes for the treatment of obesity in male mice.
    Merc Emil Matienzo, Junhyeong Lee, Sangyi Lim, Edzel Evallo, Chang-Min Lee, Keon Kim, Min-Jung Park, Dong-Il Kim.
      Glucocorticoids (GCs) are potent regulators of energy balance and adipose tissue function, making them attractive targets for obesity treatments. The local activation and inactivation of GCs are mediated by two key enzymes: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates active GCs, and type 2 (11β-HSD2), which inactivates them. In this study, we explored the therapeutic potential of modulating adipose GC metabolism by targeting 11β-HSD enzymes using adeno-associated virus (AAV)- based gene delivery systems. Specifically, we employed AAV-DIO-mediated overexpression of 11β-HSD2 and CRISPR-Cas9-mediated knockout of 11β-HSD1 in adipocytes. Adipocyte-specific overexpression of 11β-HSD2 suppressed GC-responsive gene expression but did not prevent diet-induced obesity, enhance thermogenic capacity under cold exposure, or improve GC-driven metabolic dysfunction. In contrast, adipocyte-specific deletion of 11β-HSD1 reduced adiposity and ameliorated hepatic steatosis in high-fat diet-fed male mice. However, these metabolic benefits were not observed in female mice, indicating a possible sex-specific response to adipose GC modulation. These findings suggest that while 11β-HSD2 overexpression alone is insufficient to counteract GC-related metabolic dysfunction, inhibition of 11β- HSD1 may offer modest metabolic benefits in males. Overall, this study highlights the sex-dependent roles of 11β-HSD isoenzymes in adipose GC regulation and their therapeutic potential in obesity.
    Keywords:  11β-hydroxysteroid dehydrogenase; adeno-associated virus; adipocytes; glucocorticoids; obesity
    DOI:  https://doi.org/10.1152/ajpcell.00978.2024
  6. Diabetes Obes Metab. 2025 Jul 09.
    Glucagon-like peptide-1 is involved in fasting and postprandial blood flow regulation of subcutaneous adipose tissue.
    Richard Sotorník, Pascal Brassard, Julie Ménard, Maude Gagnon-Auger, Jean-Patrice Baillargeon, Jean-Luc Ardilouze.
       AIMS: Glucagon-like peptide 1 (GLP-1) is a gastrointestinal hormone with pleiotropic functions, including vasodilatory and vasculoprotective effects. As GLP-1 increases after a meal, it could be involved in adipose tissue blood flow (ATBF) regulation. In one-third of healthy people, the postprandial ATBF response to meals is blunted. Whether this responder/non-responder phenomenon stems from an incretin defect is not known. Thus, we aimed to assess the implication of GLP-1 in ATBF regulation and responder/non-responder status.
    MATERIALS AND METHODS: ATBF at the anterior abdominal wall was recorded using the 133Xenon washout technique. Fasting and post-oral glucose ATBF were assessed during local microinfusion of a GLP-1 receptor antagonist exendin(9-39). Physiological ATBF was recorded at the control saline site. Anthropometric and metabolic parameters were measured as well.
    RESULTS: Twenty-seven healthy individuals (8 men) participated, and 14 responders (ATBF increase >50% of baseline values) and 13 non-responders were identified. Compared to the control site, exendin(9-39) significantly decreased fasting (0.16 [0.41; 0.04] vs. 0.04 [0.17; 0.14] mL 100 g-1 min-1; p = 0.001) and post-glucose ATBF (iAUC: 45.2 [9.0; 150.9] vs. 49.8 [13.3; 216.6] mL 100 g-1 min-1; p < 0.001). Exendin(9-39) led to comparable relative suppression of post-glucose ATBF in responders and non-responders (20.9 [45.6; 12.2] vs. 15.1 [66.5; -0.1] %; p = 0.84). In non-responders, post-glucose triacylglycerols (TAG) were significantly higher.
    CONCLUSIONS: GLP-1 seems to be involved in ATBF regulation, which is reduced when GLP-1 action is blocked in situ, but has no role in the blunting of ATBF response in non-responders. Blunted postprandial ATBF may be implicated in higher postprandial circulating TAG levels.
    Keywords:  adipose tissue blood flow; exendin(9‐39); glucagon‐like peptide 1; incretins; triacylglycerols
    DOI:  https://doi.org/10.1111/dom.16589
  7. J Clin Invest. 2025 Jul 08. pii: e172198. [Epub ahead of print]
    Caloric Restriction Promotes Resolution of Atherosclerosis in Obese Mice, while Weight Regain Accelerates its Progression.
    Bianca Scolaro, Franziska Krautter, Emily J Brown, Aleepta Guha Ray, Rotem Kalev-Altman, Marie Petitjean, Sofie Delbare, Casey Donahoe, Stephanie Pena, Michela L Garabedian, Cyrus A Nikain, Maria Laskou, Ozlem Tufanli, Carmen Hannemann, Myriam Aouadi, Ada Weinstock, Edward A Fisher.
      While weight loss is highly recommended for those with obesity, >60% will regain their lost weight. This weight cycling is associated with elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss/regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss was found to promote atherosclerosis resolution independent of plasma cholesterol. From single-cell RNA-sequencing and subsequent mechanistic studies, this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal white adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fcgr4, help to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyper-inflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerosis resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming.
    Keywords:  Adipose tissue; Atherosclerosis; Cardiology; Inflammation; Innate immunity; Metabolism
    DOI:  https://doi.org/10.1172/JCI172198
  8. Diabetes. 2025 Jul 11. pii: db250010. [Epub ahead of print]
    Lipidomic Signatures of Insulin Resistance Identified From Hyperinsulinemic-Euglycemic Clamp Studies in Asian Men.
    Sartaj Ahmad Mir, Kothandaraman Narasimhan, Jayagowtham K Annadurai, Vaitheeswari, Shanshan Ji, David Cameron-Smith, Johan G Eriksson, Melvin Khee-Shing Leow, Markus R Wenk, Federico Torta, Chin Meng Khoo.
      Insulin resistance (IR) is fundamental to the development of type 2 diabetes and usually precedes the disease by several years. Therefore, a better understanding of the molecular pathogenesis of IR may help better manage and prevent the metabolic syndrome. We used an integrated approach of anthropometric and biochemical measures in conjunction with serum lipidomics for metabolic phenotyping of multiethnic male participants with varied insulin sensitivity. By detailed characterization of the serum lipidomic profiles in the fasting state as well as temporal changes during the hyperinsulinemic-euglycemic clamp procedure (HIEC), we identified a systemic metabolic response to the HIEC represented by the marked changes in the acylcarnitine, nonesterified fatty acid, lysophospholipid, sphingosine-1-phosphate, and phosphatidylserine lipid classes. We demonstrate that a shared lipidomic signature between IR and liver fat shows gradual increase with increasing liver fat percentage. In summary, by stratifying the study participants according to the insulin sensitivity indices derived from the HIEC procedures, we identified a circulating lipidomic signature of IR and metabolic plasticity with a potential for prediction and management of metabolic health before the development of type 2 diabetes and other metabolic diseases.
    ARTICLE HIGHLIGHTS: The underlying molecular pathogenesis of the Asian phenotype of insulin resistance remains to be understood. We carried out metabolic phenotyping of study participants without diabetes according to insulin sensitivity indices derived from hyperinsulinemic-euglycemic clamp procedures. We identified lipidomic signatures of insulin resistance and metabolic plasticity. These lipidomic signatures have the potential to help in risk stratification of insulin resistance and metabolic dysfunction for early intervention.
    DOI:  https://doi.org/10.2337/db25-0010
  9. Breast Cancer Res. 2025 Jul 06. 27(1): 125
    Hsp47 drives obesity-associated breast cancer progression by enhancing asporin deposition in adipose tissue.
    Gaofeng Xiong, Daheng He, Dana Napier, Jing Chen, Haizhu Shi, Chun Li, Paula J Hurley, Chi Wang, Haining Zhu, Changcheng Zhou, Theresa J Bocklage, Ren Xu.
      Fibrosis is an important feature of adipose tissue in obese individuals; nevertheless, roles of obesity-associated extracellular matrix (ECM) deposition in breast cancer progression largely remain elusive. Here, we show that expression of Hsp47, a chaperone protein involving collagen secretion, is induced in adipose tissue from obese humans and mice. Adipocyte-specific Hsp47 deletion (Adi-KO) suppresses the high-fat diet (HFD)-induced obesity and mammary tumor progression, accompanied by a reduction in ECM deposition. Matrisome analyses lead to the identification of asporin as a new target of Hsp47 in adipose tissue. Co-immunoprecipitation results confirm that the recruitment of Hsp47 enhances asporin secretion in adipocytes. We further show that knockout of asporin suppresses HFD-induced mammary tumor growth, while exogenous of asporin partially rescues tumor growth in the decellularized mammary gland derived from Hsp47 Adi-KO mice. These results indicate that asporin at least partially mediates Hsp47 function in HFD-associated tumor progression. Digital spatial profiling (DSP) analyses show that Hsp47 depletion significantly increases the accumulation of CD8 T cells in tumor and tumor-associated adipose tissues. These results implicate that Hsp47, along with-it mediated ECM deposition, suppresses the anti-tumor immunity under HFD conditions. These findings reveal Hsp47 as a novel target for mitigating obesity-associated breast cancer progression.
    DOI:  https://doi.org/10.1186/s13058-025-02076-9
  10. Science. 2025 Jul 10. 389(6756): 157-162
    ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
    Laura F DiGiovanni, Prabhsimran K Khroud, Ruth E Carmichael, Tina A Schrader, Shivneet K Gill, Kyla Germain, Robert Y Jomphe, Christoph Wiesinger, Maxime Boutry, Maki Kamoshita, Daniel Snider, Garret Stubbings, Rong Hua, Noel Garber, Christian Hacker, Andrew D Rutenberg, Roman A Melnyk, Johannes Berger, Michael Schrader, Brian Raught, Peter K Kim.
      Maintenance of mitochondrial redox homeostasis is of fundamental importance to cellular health. Mitochondria harbor a host of intrinsic antioxidant defenses, but the contribution of extrinsic, nonmitochondrial antioxidant mechanisms is less well understood. We found a direct role for peroxisomes in maintaining mitochondrial redox homeostasis through contact-mediated reactive oxygen species (ROS) transfer. We found that ACBD5 and PTPIP51 form a contact between peroxisomes and mitochondria. The percentage of these contacts increased during mitochondrial oxidative stress and helped to maintain mitochondrial health through the transfer of mitochondrial ROS to the peroxisome lumen. Our findings reveal a multiorganelle layer of mitochondrial antioxidant defense-suggesting a direct mechanism by which peroxisomes contribute to mitochondrial health-and broaden the scope of known membrane contact site functions.
    DOI:  https://doi.org/10.1126/science.adn2804
  11. bioRxiv. 2025 Jul 05. pii: 2025.07.01.662587. [Epub ahead of print]
    Morning Elevation in Insulin Enhances Afternoon Postprandial Insulin Action and Glucose Effectiveness.
    Hannah L Waterman, Marta S Smith, Ben Farmer, Kalisha Yankey, Tristan Howard, Guillaume Kraft, Alan D Cherrington, Dale S Edgerton.
      The second meal phenomenon refers to the improved glycemic response observed after consuming a second identical meal. It is well known that postprandial hepatic glucose uptake (HGU) is determined by the combined effects of three regulatory factors: insulin action (hyperinsulinemia; HI), glucose effectiveness (hyperglycemia; GE), and glucose delivery into the hepatoportal circulation (portal glucose signal; PGS). While our previous studies demonstrated the importance of morning (AM) hyperinsulinemia in priming the liver for increased HGU later in the day, the question remains as to which aspect of the afternoon (PM) response is enhanced by morning insulin. Thus, to provide insight into the underlying mechanism of the 2 nd meal effect, we sought to determine the extent to which PM HI, GE, and the PGS are impacted by AM hyperinsulinemia. Dogs underwent an AM clamp with either a 4h hyperinsulinemic prime (Prime, n=8 ) or basal insulin delivery (No Prime, n=8 ). After a 1.5h non-clamp period, both groups were challenged with a PM hyperglycemic clamp (with the PGS) in the presence of basal insulin. During the PM clamp, net HGU was significantly elevated in Prime vs. No Prime group (mean of 2.2±0.3 vs. 0.1±0.3 mg/kg/min, respectively, P<0.005), indicating an enhancement of GE and/or the PGS. There was no difference in PM non-HGU (4.5±0.3 vs. 4.0±0.3 mg/kg/min). In previous experiments, when all three factors (HI, GE, PGS) were present in the PM, net HGU was 6.3±1.7 vs. 2.4±1.1 mg/kg/min in groups receiving an AM insulin prime vs. basal insulin, respectively. Therefore, the AM insulin prime enhanced the effects of HI, GE, and the PGS on PM HGU by 3.9 mg/kg/min, whereas it enhanced the effects of glucose (GE and the PGS), in the absence of a rise in insulin, by 2.1 mg/kg/min. Taken together, the data show that AM HI enhanced PM insulin action and GE (including the PGS) to an equal extent. This suggests that AM insulin priming enhances cellular targets common to both insulin and glucose signaling in the PM.
    DOI:  https://doi.org/10.1101/2025.07.01.662587
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