bims-mimead Biomed News
on Adipose tissue and metabolic disease
Issue of 2025–09–28
eight papers selected by
Rachel M. Handy, University of Guelph



  1. Diabetes. 2025 Sep 22. pii: db250492. [Epub ahead of print]
      Subcellular lipid accumulation and intermuscular adipose tissue (IMAT) accumulation are associated with insulin resistance, but the impact of combined weight loss and exercise training on localization of lipids and IMAT cellular composition is not known. Twenty-one adults with obesity (18 female and 3 male; 46 ± 2 years; 35.0 ± 0.9 kg/m2) completed a 3-month supervised weight loss and exercise training intervention. Insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp, and basal and insulin-stimulated vastus lateralis biopsies were collected pre- and postintervention. After the intervention, body weight and body fat decreased (11 ± 1% and 9 ± 1%, respectively), while VO2 peak and insulin sensitivity increased (14 ± 3% and 68 ± 14%, respectively). Lipidomics revealed reduced sarcolemmal and nuclear triglycerides, with unchanged whole-muscle triglycerides. Whole-muscle diacylglycerols increased because of increased nuclear 1,2-diacylglycerols without PKCε, PKCθ, or PKCδ activation. Whole-muscle sphingolipid levels increased because of cytosolic accumulation. Single-nuclei RNA sequencing showed altered IMAT cellular composition, including increased fibro-adipogenic progenitors, vascular cells, and macrophages, and decreased preadipocytes. Bulk muscle RNA sequencing indicated upregulation of genes related to muscle remodeling and cellular respiration, and there were changes in the relationship between nuclear diacylglycerols and gene expression postintervention. These findings dissociate improvements in insulin sensitivity from total muscle diacylglycerol and sphingolipid levels and highlight roles for subcellular lipid redistribution and IMAT remodeling in insulin sensitization.
    ARTICLE HIGHLIGHTS: Evaluation of subcellular fractionated muscle revealed decreases in sarcolemmal and nuclear triglycerides and increases in nuclear diacylglycerols and cytosolic sphingolipids postintervention. Weight loss revealed alteration in the cellular composition of intermuscular adipose tissue and upregulation of genes related to muscle remodeling and cellular respiration. These findings dissociate improvements in insulin sensitivity from total muscle 1,2-diacylglycerol and sphingolipid levels and highlight roles of intermuscular adipose tissue remodeling for enhanced insulin sensitivity.
    DOI:  https://doi.org/10.2337/db25-0492
  2. J Endocr Soc. 2025 Oct;9(10): bvaf134
       Context: We created an innovative mouse model that enables inducible overexpression of estrogen receptor-alpha (ERα), specifically in adipose tissue (Adipo-ERα↑).
    Objective: We aimed to investigate how elevated Adipo-ERα↑ influences the development of high-fat diet (HFD)-induced obesity in both male and female mice.
    Methods: Male and female Adipo-ERα↑ mice and littermate controls were fed a low-fat diet (LFD) or HFD for 13 weeks. Adipo-ERα↑ was induced at the initiation of dietary treatment. Body morphology and composition, hepatic lipid accumulation, glucose tolerance, fasting insulin concentrations, and adipose tissue mRNA profiling were assessed. Liquid chromatography-mass spectrometry was used to determine circulating and adipose tissue sex steroid content.
    Results: Adipo-ERα↑ significantly reduced adiposity and hepatic lipid accumulation in HFD-fed female mice but not in male mice. However, in both sexes, Adipo-ERα↑ greatly reduced adipose tissue inflammation characteristic of obesity. Despite these effects, Adipo-ERα↑ did not improve glucose tolerance or fasting insulin levels and did not affect circulating and adipose tissue sex steroid content.
    Conclusion: Adipo-ERα↑ elicits distinct sex-specific effects with respect to body composition and hepatic lipid accumulation, which are likely driven by variations in circulating and tissue estrogen levels. Nonetheless, despite differences in estrogen levels, Adipo-ERα↑ profoundly reduced obesity-linked adipose tissue inflammation in both sexes, providing further evidence that therapeutically targeting ERα may be beneficial for treating obesity-associated inflammation.
    Keywords:  adipose tissue; estrogen; estrogen receptor-alpha; inflammation; obesity
    DOI:  https://doi.org/10.1210/jendso/bvaf134
  3. Nat Metab. 2025 Sep;7(9): 1765-1780
    International Indirect Calorimetry Consensus Committee (IICCC)
      Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations.
    DOI:  https://doi.org/10.1038/s42255-025-01360-4
  4. Exerc Sport Sci Rev. 2025 Oct 01. 53(4): 195-204
      In this review, we hypothesize that delaying physical training initiation until several years after menopause reduces the benefits of exercise on muscle function and cardiovascular health. Early engagement in exercise may counteract the negative effects of estradiol loss by activating pathways with similar molecular targets as estrogen, thereby helping to preserve muscle function and cardiovascular health during the postmenopausal period.
    Keywords:  cardiovascular health; estrogen; estrogen receptors; estrogen-related receptor alpha; exercise training; menopause; muscle function
    DOI:  https://doi.org/10.1249/JES.0000000000000371
  5. Obesity (Silver Spring). 2025 Sep 25.
       OBJECTIVE: Incretin-based obesity medication maintains weight loss by mimicking the appetite-inhibiting hormone GLP-1. Interestingly, chronic exercise may improve postprandial appetite control by increasing late postprandial secretion of endogenous GLP-1. Therefore, we investigated whether an exercise program after weight loss could increase late-phase postprandial GLP-1 secretion.
    METHODS: This study is an exploratory analysis of adults with obesity (n = 195) who lost 13.1 kg on a low-calorie diet and were randomized to 52 weeks of either usual activity, moderate-to-vigorous intensity exercise, the GLP-1 receptor agonist liraglutide (3.0 mg/day), or the combination. The primary endpoint was change in late-phase GLP-1 response to a 3-h liquid mixed meal test before and after diet-induced weight loss and after 1 year of intervention.
    RESULTS: Diet-induced weight loss did not change late-phase GLP-1 response (3%; 95% CI, -4%-10%). One year of exercise increased late-phase postprandial GLP-1 response within the group by 37% (95% CI, 20%-57%), and this increase was 25% greater (95% CI, 3%-51%, p = 0.02) compared to the usual activity group. Late-phase postprandial GLP-1 response was unchanged in both groups treated with GLP-1 receptor agonist compared to placebo.
    CONCLUSIONS: One year of exercise increased late-phase postprandial GLP-1 response, which may prevent increased appetite after weight loss and thereby weight regain.
    TRIAL REGISTRATION: EudraCT number: 2015-005585-32; ClinicalTrials.gov identifier: NCT04122716.
    Keywords:  GLP‐1; appetite regulation; exercise; obesity; weight loss
    DOI:  https://doi.org/10.1002/oby.70043
  6. Metabolism. 2025 Sep 20. pii: S0026-0495(25)00265-3. [Epub ahead of print] 156396
      Contemporary lifestyle modifications such as changes in nutritional and sleep/wake rhythms increase the risk of metabolic and inflammatory complications linked to obesity, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). BMAL2 (Brain and Muscle ARNT Like Protein 2) is a transcription factor belonging to the circadian clock transcriptional feedback loop which synchronizes internal biological rhythms to environment. In humans, reduced expression in white adipose tissue (WAT) and specific polymorphisms of BMAL2 are associated with obesity and T2D. In this study we report that Bmal2 deletion in mice leads to increased body weight gain during diet-induced obesity. Loss of BMAL2 triggers the inflammatory response by increasing Tnfα expression and modifying adipocyte progenitor fate. This results in reduced lipid storage capacity within the WAT and increased ectopic storage in the liver. These functional and structural alterations culminate in the onset of hepatic steatosis and insulin resistance in liver and WAT. Overall, our investigations underscore the role of BMAL2 in the development and function of adipocytes, as well as in their inflammatory potential within the WAT. Our findings contribute to the understanding of the role of circadian clock genes in obesity and interconnected metabolic complications.
    Keywords:  Adipose tissue; Circadian rhythm; Inflammation; Obesity; Preadipocytes
    DOI:  https://doi.org/10.1016/j.metabol.2025.156396
  7. J Physiol. 2025 Sep 22.
      Semaglutide is a GLP-1 receptor agonist that is highly efficacious in reducing food intake and body weight. While semaglutide reduces adipose tissue, there is also a loss of lean mass including skeletal muscle, though it is unclear whether this translates to a loss of muscle function. The effect of discontinuation of semaglutide on rebound weight gain and shifts in body composition is also not well understood. We investigated the impact of semaglutide and matched caloric restriction on body composition in mice with diet-induced obesity. Mice were treated with semaglutide or fed a calorie-matched diet for 4 weeks. Semaglutide and pair-feeding induced significant weight loss with a concomitant reduction in energy expenditure. Weight loss was greater with semaglutide than caloric restriction, despite matched energy intake. Muscle transcriptomic analyses revealed distinct molecular responses between semaglutide and pair-feeding. In a follow-up experiment, semaglutide and pair-feeding was discontinued after 4 weeks, and body weight and food intake were tracked for 6 weeks. At the end of the withdrawal period there was a loss of treatment effects. Lean and fat mass rebounded to baseline levels at the end of the withdrawal period. Muscle size and strength were also comparable between groups. These findings demonstrate that semaglutide reduces muscle size and strength to the same extent as caloric restriction but may be more effective at promoting fat loss. Interestingly, the loss of lean mass and skeletal muscle recovered following treatment discontinuation. KEY POINTS: Semaglutide results in greater weight loss than caloric restriction. Semaglutide treatment increases fat loss compared with caloric restriction. Muscle mass and strength is reduced to a similar extent by semaglutide and restricted feeding.
    Keywords:  obesity; semaglutide; skeletal muscle; weight loss
    DOI:  https://doi.org/10.1113/JP289449
  8. Aging Cell. 2025 Sep 26. e70247
      Mitochondrial calcium (Ca2+) homeostasis plays a critical role in aging and cellular fitness. In the search for novel antiaging approaches, we explored how genetic and pharmacological inhibition of mitochondrial Ca2+ uptake influences the lifespan and health of Caenorhabditis elegans. Using live-cell imaging, we demonstrate that RNA interference-mediated knockdown of mcu-1, the nematode ortholog of the mitochondrial Ca2+ uniporter (MCU), reduces mitochondrial Ca2+ levels, thereby extending lifespan and preserving motility during aging, while compromising early-life survival. This longevity benefit requires intervention before day 14 and coincides with a transient increase in reactive oxygen species (ROS), which activates pathways involving pmk-1, daf-16, and skn-1, orthologs of human p38 mitogen-activated protein kinase (p38 MAPK), forkhead box O (FOXO), and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. This pathway promotes antioxidant defense mechanisms and preserves mitochondrial structure and function during aging, maintaining larger, more interconnected mitochondria and restoring the oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio and oxygen consumption rates to youthful levels. Pharmacological inhibition of mitochondrial Ca2+ uptake using the MCU inhibitor mitoxantrone mirrors the effects of mcu-1 knockdown, extending lifespan and improving fitness in aged nematodes. In human foreskin fibroblasts, short-term mitoxantrone treatment also transiently elevates ROS production and induces enhanced expression and activity of antioxidant defense enzymes, underscoring the translational relevance of findings from nematodes to human cells. Our findings suggest that modulation of mitochondrial Ca2+ uptake induces mitohormesis through ROS-mediated signaling, promoting improved longevity and healthspan in nematodes, with possible implications for healthy aging in humans.
    Keywords:   C. elegans ; aging; lifespan; longevity; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1111/acel.70247