bims-mimead 2025-08-10 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–08–10
seven papers selected by
Rachel M. Handy, University of Guelph

Combined Deletion of miR-27a and miR-27b Enhances Protection Against Diet-Induced Obesity.
Hematopoietic stem cell-derived adipocytes suppress leptin production, and attenuate ovariectomy-induced inhibition of physical activity and insulin sensitivity in female mice.
Effects of β-catenin deficiency on adipose tissue physiology.
Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue.
Diet-Induced Obesity Disrupts Sexually Dimorphic Gene Expression in Mice.
Tissue-specific and whole-body insulin sensitivity by integrated imaging and hyperinsulinemic euglycemic clamp: A repeatability study in people with T2DM and overweight/obesity.
Pharmacological weight loss with incretin-based therapies does not result in a disproportionate loss of muscle mass or function in obese mice and humans.

bioRxiv. 2025 Jul 25. pii: 2025.07.21.666011. [Epub ahead of print]

Combined Deletion of miR-27a and miR-27b Enhances Protection Against Diet-Induced Obesity.

Devesh Kesharwani, Michele Karolak, Chad C Doucette, Eric R Loomis, Su Su, Aaron C Brown.

Obesity impairs adipose tissue thermogenesis, contributing to metabolic dysfunction. Here, we identify miR-27a and miR-27b as cooperative regulators of adipose tissue thermogenesis and adipogenic programming in the context of diet-induced obesity (DIO). Intervention of high-fat diet (HFD) to mice suppressed the expression of Ucp1, Ppary , and Pgc1a in inguinal white adipose tissue (WAT), which correlated with the increased expression of miR-27a/b. Using global knockout models for miR-27a and miR-27b, we identified that combined deletion of both miRNAs (double knockout, DKO) synergistically enhances Ucp1 expression, mitochondrial heat production and browning of WAT. DKO mice displayed improved glucose, insulin sensitivity and reduced adiposity under HFD conditions and outperformed single knockouts. In-vitro and ex-vivo analysis confirmed an increase in thermogenic gene expression and reduced lipid accumulation in DKO adipocytes. Collectively, our findings reveal that miR-27a/b cooperatively suppresses adipose thermogenesis and promotes metabolic dysfunction under obesogenic conditions. Targeting the miR-27a/b axis may offer a novel therapeutic approach to enhance energy expenditure and combat obesity-related metabolic diseases.

DOI: https://doi.org/10.1101/2025.07.21.666011
Adipocyte. 2025 Dec;14(1): 2536813

Hematopoietic stem cell-derived adipocytes suppress leptin production, and attenuate ovariectomy-induced inhibition of physical activity and insulin sensitivity in female mice.

Andrew E Libby, Timothy M Sullivan, Joanne K Maltzahn, Matthew R Jackman, Kathleen M Gavin, Paul S MacLean, Wendy M Kohrt, Susan M Majka, Dwight J Klemm.

  A subpopulation of adipocytes in mice and humans is produced from haematopoietic stem cells rather than mesenchymal progenitors; the source of conventional white and brown/beige adipocytes. The abundance of these haematopoietic stem cell-derived adipocytes (HSCDAs) is elevated in female mice by ovariectomy (OVX) or oestrogen receptor alpha (ERα) knockdown, suggesting that they may be involved in the metabolic and inflammatory pathology that accompany the loss of oestrogen signalling. However, we previously demonstrated that ablation of HSCDAs elevated circulating leptin levels while suppressing physical activity and insulin sensitivity. Here, we tested the combined impact of OVX with and without HSCDA ablation. We discovered that HSCDA depletion plus OVX raised circulating leptin levels more than HSCDA depletion alone. Likewise, while HSCDA depletion or OVX alone inhibited physical activity and insulin responsiveness, their combination further suppressed these endpoints. Other physiologic endpoints were regulated by OVX alone. We conclude that HSCDAs play a role inthe maintenance of a subset of metabolic endpoints related to normal adipose tissue function, and their elevated production in models of female sex hormone suppression occurs to normalize these endpoints. The results highlight the ability of HSCDAs to target physical activity and insulin responsiveness, possibly by normalizing leptin production.

Keywords:  Adipose tissue biology; adipose stem cells; animal models; energy expenditure; reproductive hormones

DOI:  https://doi.org/10.1080/21623945.2025.2536813
Mol Metab. 2025 Aug 02. pii: S2212-8778(25)00133-4. [Epub ahead of print] 102226

Effects of β-catenin deficiency on adipose tissue physiology.

Romina M Uranga, Akira Nishii, Jessica N Maung, Hiroyuki Mori, Brian Desrosiers, Jannis Jacobs, Keegan S Hoose, Rebecca L Schill, Devika P Bagchi, Hannah Guak, Clair Crewe, Ivo D Dinov, Erin D Giles, Carey N Lumeng, Ormond A MacDougald.

   OBJECTIVE: Compelling evidence from investigation of preclinical models and humans links canonical Wnt/β-catenin signaling to regulation of many aspects of white adipose tissue development and physiology. Dysregulation of this ancient pathway alters adiposity and metabolic homeostasis. Herein we explore how disruption of adipocyte Wnt/β-catenin signaling affects gene expression and crosstalk between cell types within adipose tissue.
METHODS: To investigate mechanisms through which adipose tissue attempts to maintain homeostasis in the absence of β-catenin in adipocytes, we employed standard methods of metabolic phenotyping as well as bulk RNA sequencing, flow cytometry, single-cell RNA sequencing, and isolation of secreted extracellular vesicles.
RESULTS: Our experiments reveal that male, but not female adipocyte-specific β-catenin knockout mice, Ctnnb1AdKO, have an increase in adiposity and insulin resistance. Whereas metabolic processes including fatty acid metabolism were suppressed in adipocytes, mitochondrial metabolism of immune cells was made more efficient, resulting in reduced reactive oxygen species in macrophages and dendritic cells. Deficiency of β-catenin in adipocytes altered the transcriptome of numerous stromal-vascular cell populations including adipose stem and progenitor cells, macrophages, and other immune cells. Homeostasis in white adipose tissue of Ctnnb1AdKO mice is maintained in part by elevated expression of Ctnnb1 mRNA in endothelial cells and in secreted small extracellular vesicles.
CONCLUSIONS: Our studies demonstrate the importance of adipocyte Wnt signaling for regulation of lipid and mitochondrial metabolic processes in stromal-vascular cells and adipocytes in adipose tissues. This research provides further support for an intercellular Wnt signaling network with compensatory capability to maintain homeostasis, and underscores importance of Wnt/β-catenin signaling for understanding adipose tissue physiology and pathophysiology.

Keywords:  Wnt signaling; adipocyte; adipose; extracellular vesicles; macrophages; mitochondria; reactive oxygen species; β-catenin

DOI:  https://doi.org/10.1016/j.molmet.2025.102226
Mol Metab. 2025 Aug 01. pii: S2212-8778(25)00134-6. [Epub ahead of print] 102227

Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue.

Dorota Kaminska, Calvin Pan, Laurent Vergnes, Ashlyn Ro, Gurugowtham Ulaganathan, Aldons J Lusis.

OBJECTIVE: Sex differences in adipose tissue impact metabolic health, but the underlying molecular mechanisms remain unclear. We previously identified a female-specific chr17 trans-eQTL hotspot regulating mitochondrial gene expression in gonadal white adipose tissue (gWAT). Here, we tested whether iWAT contributes comparably to sex differences in mitochondrial function and futile cycling.
METHODS: We analyzed iWAT and gWAT from male and female mice across 58 genetically diverse Hybrid Mouse Diversity Panel (HMDP) strains fed a high-fat, high-sucrose diet. We assessed mitochondrial DNA (mtDNA), oxidative phosphorylation (OXPHOS) and futile cycle gene expression, performed genetic mapping, and measured respiration.
RESULTS: In gWAT, females showed higher mtDNA, OXPHOS expression, and a female-specific chr17 trans-eQTL, correlating with metabolic traits. In contrast, iWAT lacked this hotspot and showed higher mtDNA, OXPHOS expression, and respiration in males. Lipid cycling genes (Lipe, Mgll, Pnpla2) were elevated in male iWAT, while Mpc1, Mpc2, and Pck1 were enriched in female gWAT. Ucp1 was higher in female gWAT but not sex-biased in iWAT. Alpl (TNAP), key creatine cycling gene, was upregulated in females in both depots, particularly in iWAT.
CONCLUSIONS: Female gWAT shows genetically driven mitochondrial regulation linked to metabolic protection, whereas male iWAT has higher mitochondrial content, OXPHOS expression, and respiration. Elevated lipolytic enzymes in male iWAT suggest greater FFA release, while higher pyruvate import and glyceroneogenesis genes in female gWAT favor FFA recycling. Alpl upregulation in females indicates sex-biased UCP1-independent thermogenesis. These depot- and sex-specific signatures reflect distinct metabolic strategies and highlight the need to consider both in adipose research.

DOI: https://doi.org/10.1016/j.molmet.2025.102227
Am J Physiol Cell Physiol. 2025 Aug 04.

Diet-Induced Obesity Disrupts Sexually Dimorphic Gene Expression in Mice.

Vicent Ribas, Samantha Morón-Ros, Helena Mari, Albert Gracia-Batllori, Laura Brugnara, Alba Herrero-Gomez, Elena Eyre, Marc Claret, Irene Marco-Rius, Anna Novials, Joan-Marc Servitja.

  Biological sex significantly influences the prevalence, incidence, and severity of numerous human diseases, yet it remains an underappreciated variable in biomedical research. While sexually dimorphic genes contribute to sex-specific traits and disease manifestations, their regulation under metabolic stress is poorly understood. To explore sex-specific metabolic adaptations, we analyzed responses to high-fat diet (HFD)-induced obesity in male and female mice, focusing on the regulation of sex-biased genes. Despite similar adiposity, HFD-fed males displayed more severe metabolic impairments than females, highlighting divergent metabolic outcomes. To investigate the basis for these sex-specific differences, we performed whole transcriptomic profiling of liver and white adipose tissue (WAT) at early (2 weeks) and late (12 weeks) stages of HFD exposure. Our analysis revealed marked sex-specific gene expression changes across multiple categories, particularly pronounced in male WAT after prolonged HFD feeding. Strikingly, genes exhibiting sexual dimorphism under normal conditions were preferentially modulated in both sexes, comprising up to 46% of all HFD-regulated genes. This led to a substantial loss of sex-biased gene expression in both liver and WAT after HFD exposure, correlating with metabolic dysfunction. Male-biased genes associated with cilia function and estrogen response were among the most affected, showing significant downregulation in male WAT under HFD. Our findings provide a novel perspective on how obesity disrupts sex-specific gene expression in key metabolic tissues, particularly targeting sex-biased genes. By revealing that a considerable proportion of sex-biased genes exhibit HFD-regulated modulation, our study highlights the critical role of these genes in maintaining metabolic health.

Keywords:  Type 2 diabetes; insulin resistance; obesity; sex differences; transcriptomics

DOI:  https://doi.org/10.1152/ajpcell.00098.2025
EJNMMI Res. 2025 Aug 07. 15(1): 105

Tissue-specific and whole-body insulin sensitivity by integrated imaging and hyperinsulinemic euglycemic clamp: A repeatability study in people with T2DM and overweight/obesity.

Iina Laitinen, Helena Litorp, Folke Sjöberg, Simon Ekström, Henrik Haraldsson, Stefan Pierrou, Alexander Korenyushkin, Joel Kullberg, Sudeepti Southekal, Ming Lu, Tamer Coskun, Zvonko Milicevic, Lars Johansson.

   BACKGROUND: Assessment of glucose uptake by PET imaging under hyperinsulinemic euglycemic clamp (HEC) is an insightful tool for quantification of insulin resistance, a hallmark of diabetes and an area of interest in drug development. To enable the use of the method in metabolic trials, the repeatability of dynamic whole-body PET/MRI assessments of the tissue-specific glucose uptake and the total body glucose utilisation were investigated. The study included participants with type 2 diabetes mellitus (T2DM) and overweight/obesity, for two repeated examinations in standardised conditions. All participants signed informed consent, and the study plan was approved by the Swedish Ethical Review Authority (#2020-04140). After an overnight fast, HEC was established and a series of [18F]FDG-PET/MRI scans were performed. Total body glucose utilisation (M-value) was calculated for the duration of the scan and the tissue-specific metabolic rates of glucose uptake (MRGlu) were calculated using Patlak model. The repeatability was assessed by calculating the intraclass correlation coefficient (ICC).
RESULTS: Repeatability was assessed in per protocol set of 12 participants (PPS, defined by a consistent HEC) and in full analysis set (FAS n = 16). The measured M-values and tissue MRGlu demonstrated varying levels of insulin resistance. M-value ICC was 0.95 (95% CI 0.86-0.99) for PPS, indicating excellent repeatability. Tissue-specific MRGlu repeatability was excellent for skeletal muscle (ICC 0.94), and good to at least fair for SAT, VAT, myocardium, and brain. The FAS had lower, but at least fair repeatability, emphasising the importance of standardisation in metabolic assessments.
CONCLUSION: Dynamic [18F]FDG-PET/MRI provides quantitative information on tissue-specific insulin sensitivity during hyperinsulinemic euglycemic clamp with a reliability comparable to total body glucose utilisation assessment. The method has potential to add value in monitoring and evaluating T2DM treatment effects on glucose uptake and insulin resistance in interventional trials.

Keywords:  FDG; Insulin resistance; PET/MRI; Repeatability; T2DM

DOI:  https://doi.org/10.1186/s13550-025-01298-4
medRxiv. 2025 Jul 28. pii: 2025.07.28.25332295. [Epub ahead of print]

Pharmacological weight loss with incretin-based therapies does not result in a disproportionate loss of muscle mass or function in obese mice and humans.

Henning Tim Langer, Natalie K Gilmore, Chris M T Hayden, Julien Roux, Bruno Bariohay, Thaïs Rhouquet, Manar Awada, Julie Marcotorchino, Lorrine Bournot, Elizabeth Nunn, Paul M Titchenell, Daniela Liskiewicz, Timo D Müller, Oluwaseun Anyiam, Philip J Atherton, Iskandar Idris, Natalia Haritonow, Kristina Norman, Ursula Müller-Werdan, Keith Baar.

The new generation of incretin-based therapies are potent anti-obesity medications (AOMs) that offer the first non-surgical treatment for 936 million patients globally suffering from being overweight or obese[1]. However, clinical data suggest that incretin-mimetics could cause a disproportionate decrease in lean body mass (LBM) [2, 3], raising a concern for deterioration of skeletal muscle and acceleration of sarcopenic obesity[4]. Unfortunately, muscle mass and function are not routinely assessed in obesity studies and original data on the matter remains sparse. In this work, we conducted various pre-clinical studies and a proof-of-concept clinical trial to examine how skeletal muscle is affected by AOMs. We found that in mice with diet-induced obesity (DIO), incretin-based therapies result predominantly in a substantial decrease in fat mass alongside a small but significant decrease in LBM. Among the lean tissues, the decrease in liver mass exceeded the change in muscle mass robustly. While absolute muscle mass did decrease, relative muscle mass (i.e., the muscle mass to body weight (BW) ratio) improved significantly. Similarly, we found that absolute muscle strength decreased mildly but increased relative to the BW of mice. The relative preservation of muscle was also associated with marked improvement in running performance. Additionally, during a scenario of extreme muscle wasting (i.e., immobilization), DIO mice on incretin-based therapies did not experience more muscle loss than calorie-matched, pair-fed mice. Finally, in our clinical proof-of-concept trial, patients on AOMs significantly decreased BW, which was accompanied by a mild decrease in absolute LBM but an improvement in relative LBM. Muscle function as indicated by maximum voluntary contraction (MVC) did not decrease. Overall, these data suggest that in middle-aged obese mice and men, incretin-based therapies do cause a mild decrease in absolute muscle mass and strength that is offset by a more pronounced decrease in fat and liver mass, resulting in an improved muscle to BW ratio, function, and mobility.

DOI: https://doi.org/10.1101/2025.07.28.25332295