bims-mimead 2025-04-27 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–04–27
seven papers selected by
Rachel M. Handy, University of Guelph

Plasma endotrophin levels correlate with insulin resistance in people with obesity.
Analysis of multiple insulin actions in single muscle fibres from insulin resistant mice reveals selective defect in endogenous GLUT4 translocation.
MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes.
SVF mediates immunometabolic alterations in burn-induced hypermetabolic adipose tissue via mitochondrial transfer.
Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.
Ketogenesis mitigates metabolic dysfunction-associated steatotic liver disease through mechanisms that extend beyond fat oxidation.
Identifying four obesity axes through integrative multi-omics and imaging analysis.

J Clin Invest. 2025 Apr 22. pii: e190577. [Epub ahead of print]

Plasma endotrophin levels correlate with insulin resistance in people with obesity.

Gordon I Smith, Samuel Klein.

   BACKGROUND: Adipose tissue-derived endotrophin, a peptide cleaved from the α3 chain of collagen VI during fibrogenesis, causes systemic insulin resistance in rodent models. Here, we evaluated the potential importance of endotrophin in regulating whole-body insulin sensitivity in people.
METHODS: We evaluated: i) plasma endotrophin concentration, insulin sensitivity (assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose tracer infusion) and adipose tissue expression of genes involved in endotrophin production in three groups of participants that were rigorously stratified by adiposity and insulin sensitivity [lean insulin-sensitive (Lean-IS; n=10), obese insulin-sensitive (Obese-IS; n=10), and obesity insulin-resistant (Obese-IR; n=10)]; ii) plasma endotrophin concentration and insulin sensitivity in 15 people with obesity and type 2 diabetes before and after marked (~18%) weight loss; and iii) the effect of endotrophin on insulin signaling (AKTser473 phosporylation) and insulin action (insulin-stimulated glucose uptake) in primary human skeletal muscle myotubes.
RESULTS: Plasma endotrophin progressively increased from the Lean-IS to the Obese-IS to the Obese-IR group, was negatively associated with insulin sensitivity and positively associated with factors involved in adipose tissue endotrophin production, namely adipose tissue gene expression of matrix metalloproteinases and markers of hypoxia, inflammation, and fibrosis. Marked weight loss increased insulin sensitivity in conjunction with a decrease in plasma endotrophin concentration. Endotrophin inhibited insulin insulin-stimulated AKTser473 phosphorylation and insulin-stimulated glucose uptake in myotubes, which was restored by incubation with a neutralizing endotrophin antibody.
CONCLUSIONS: These results suggest plasma endotrophin is both a biomarker and cause of whole-body insulin resistance in people with obesity.

Keywords:  Adipose tissue; Clinical Research; Extracellular matrix; Insulin; Metabolism; Muscle biology

DOI:  https://doi.org/10.1172/JCI190577
Diabetes. 2025 Apr 24. pii: db250022. [Epub ahead of print]

Analysis of multiple insulin actions in single muscle fibres from insulin resistant mice reveals selective defect in endogenous GLUT4 translocation.

Sebastian Judge, Stewart Wc Masson, Søren Madsen, Meg Potter, David E James, James G Burchfield, Alexis Diaz-Vegas.

Accurate measurement of GLUT4 translocation is crucial for understanding insulin resistance in skeletal muscle, a key factor in the development of metabolic diseases. However, current methods rely on overexpressed epitope-tagged GLUT4 constructs or indirect measurements, limiting their physiological relevance and applicability. To overcome these challenges, we developed an innovative high-sensitivity imaging-based method that enables the direct assessment of endogenous GLUT4 translocation in primary skeletal muscle fibres. This approach utilises antibodies targeting exofacial epitopes on native GLUT4. Our method allows multiplexed analysis of multiple insulin-sensitive processes, including transferrin receptor trafficking and FOXO nuclear exclusion, alongside mitochondrial oxidative stress. This comprehensive approach provides a unique opportunity to simultaneously assess insulin action across different signalling branches within individual muscle fibres. We validated this method across multiple inbred mouse strains and models of insulin resistance, including chronic insulin exposure, palmitate treatment, and high-fat diet-induced obesity. Notably, we identified a selective defect in GLUT4 trafficking in insulin-resistant muscle fibres, while other insulin-dependent processes remained intact. By offering a high-fidelity model that maintains physiological relevance, this novel approach represents a significant advancement in the study of skeletal muscle insulin resistance and provides a powerful tool for dissecting gene-environment interactions that underlpin metabolic disease.

DOI: https://doi.org/10.2337/db25-0022
Proc Natl Acad Sci U S A. 2025 Apr 29. 122(17): e2424741122

MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes.

Miki Nishio, Keiko Yamaguchi, Junji Otani, Katsuya Yuguchi, Daisuke Kohno, Tsutomu Sasaki, Tadahiro Kitamura, Masakazu Shinohara, Tomoyoshi Soga, Koichi Kawamura, Atsuo T Sasaki, Masashi Oshima, Hiroki Hikasa, Minna Woo, Takehiko Sasaki, Hiroshi Nishina, Kazuwa Nakao, Tomohiko Maehama, Akira Suzuki.

  There is currently a global epidemic of obesity and obesity-related diseases such as type 2 diabetes due to decreased physical activity, excessive food intake, and/or genetic predisposition. The Hippo-YAP1 pathway has attracted attention as a potential therapeutic target because YAP1/TAZ activation in murine immature adipocytes in vitro suppresses their differentiation by inhibiting PPARγ activity. However, the role of YAP1 activation in mature adipocytes in vivo remains unclear. MOB1, whose expression is increased in obesity, is the hub of the Hippo core molecule complex and negatively regulates YAP1/TAZ activation. Therefore, we generated aMob1DKO mutant mice, which feature deficiency of Mob1a/b specifically in mature adipocytes. Compared to controls, aMob1DKO mice subjected to a high-fat diet showed beneficial changes consistent with resistance to diet-induced obesity. The mutants exhibited increases in basal lipolysis, "beiging," and energy expenditure, as well as suppression of ROS production and inflammation in white adipose tissue. Insulin sensitivity and glucose tolerance were improved, and ectopic fat accumulation was reduced. Most of these changes were dependent on the YAP1 activation observed in mature white adipose tissue of aMob1DKO mice. FGF21, which improves lipid metabolism, was upregulated directly via YAP1 activation, and many of the phenotypes seen in aMob1DKO mice were also dependent on FGF21. Thus, the aMob1DKO mouse is an interesting model for the study of the metabolic effects of diet-induced obesity and protection against diabetes. Our work suggests that a YAP1-FGF21 axis exists in adipocytes that may be a potential therapeutic target for obesity.

Keywords:  MOB1-YAP1-FGF21-OPA1 axis; adipocytes; diabetes; obesity

DOI:  https://doi.org/10.1073/pnas.2424741122
Shock. 2025 Apr 16.

SVF mediates immunometabolic alterations in burn-induced hypermetabolic adipose tissue via mitochondrial transfer.

Lauar de Brito Monteiro, Shayahati Bieerkehazhi, Ayesha Aijaz, Carly M Knuth, Graham Rix, Ju Hee Lee, Hoon-Ki Sung, Mahmoud Farahat, Marc G Jeschke.

   ABSTRACT: Adipose tissue (AT) browning promotes systemic alterations in energy expenditure as a response to catecholamine-induced hypermetabolism in severe burn trauma. The AT is composed of the stromal vascular fraction (SVF) and adipocytes. SVF contains a vast population of immune cells that maintain AT homeostasis. Despite evidence that local immune cell accumulation contributes to hypermetabolism, the underlying mechanism of persistent browning response is not known. Thus, we hypothesized that a specific cellular communication between adipocytes and SVF can mediate the severe metabolic alterations associated with hypermetabolism. Therefore, we used a murine burn model to show that post-burn hypermetabolism compromises mitochondria respiration and alters the immune cell profile of the AT-SVF. We found that adipocyte-derived signals promote metabolic reprogramming and inflammatory responses by SVF after burns in both mice and humans. Interestingly, adipocytes transfer mitochondria to cells in the SVF including different immune cells (macrophages, T cells, B cells) uptake mitochondria from adipocytes. Such data was replicated in human samples as well. These results indicate that adipocytes play a major role in immunometabolic reprogramming following severe burns through crosstalk with the adipose immune cell population. Therefore, targeting immune cell metabolism restoration is a potential strategy to mitigate the detrimental effects of post-burn hypermetabolism on systemic energy balance.

Keywords:  Adipose tissue; Browning; Hypermetabolism; Immunometabolism; Inflammation; Mitochondria biology

DOI:  https://doi.org/10.1097/SHK.0000000000002608
Obesity (Silver Spring). 2025 May;33(5): 974-985

Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.

Ran Hee Choi, Takuya Karasawa, Cesar A Meza, J Alan Maschek, Allison M Manuel, Linda S Nikolova, Kelsey H Fisher-Wellman, James E Cox, Amandine Chaix, Katsuhiko Funai.

OBJECTIVE: Glucagon-like peptide-1 receptor agonists (e.g., semaglutide) potently induce weight loss, thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency.
METHODS: C57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rates of ATP production and oxygen (O2) consumption were measured via high-resolution respirometry and fluorometry to determine OXPHOS efficiency in muscle at these two time points.
RESULTS: Semaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O2 consumed in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (LYRM7 and TTC19; p < 0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits.
CONCLUSIONS: These data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.

DOI: https://doi.org/10.1002/oby.24274
J Clin Invest. 2025 Apr 24. pii: e191021. [Epub ahead of print]

Ketogenesis mitigates metabolic dysfunction-associated steatotic liver disease through mechanisms that extend beyond fat oxidation.

Eric D Queathem, David B Stagg, Alisa B Nelson, Alec B Chaves, Scott B Crown, Kyle Fulghum, D Andre d'Avignon, Justin R Ryder, Patrick J Bolan, Abdirahman Hayir, Jacob R Gillingham, Shannon Jannatpour, Ferrol I Rome, Ashley S Williams, Deborah M Muoio, Sayeed Ikramuddin, Curtis C Hughey, Patrycja Puchalska, Peter A Crawford.

  The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH) involves alterations in both liver-autonomous and systemic metabolism that influence the liver's balance of fat accretion and disposal. Here, we quantify the contributions of hepatic oxidative pathways to liver injury in MASLD-MASH. Using NMR spectroscopy, UHPLC-MS, and GC-MS, we performed stable-isotope tracing and formal flux modeling to quantify hepatic oxidative fluxes in humans across the spectrum of MASLD-MASH, and in mouse models of impaired ketogenesis. In humans with MASH, liver injury correlated positively with ketogenesis and total fat oxidation, but not with turnover of the tricarboxylic acid cycle. Loss-of-function mouse models demonstrated that disruption of mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting step of ketogenesis, impairs overall hepatic fat oxidation and induces a MASLD-MASH-like phenotype. Disruption of mitochondrial β-hydroxybutyrate dehydrogenase (BDH1), the terminal step of ketogenesis, also impaired fat oxidation, but surprisingly did not exacerbate steatotic liver injury. Taken together, these findings suggest that quantifiable variations in overall hepatic fat oxidation may not be a primary determinant of MASLD-to-MASH progression, but rather, that maintenance of ketogenesis could serve a protective role through additional mechanisms that extend beyond overall rates of fat oxidation.

Keywords:  Fatty acid oxidation; Hepatology; Intermediary metabolism; Metabolism; Obesity

DOI:  https://doi.org/10.1172/JCI191021
Diabetes. 2025 Apr 24. pii: db241103. [Epub ahead of print]

Identifying four obesity axes through integrative multi-omics and imaging analysis.

Chiemela S Odoemelam, Afreen Naz, Marjola Thanaj, Elena P Sorokin, Brandon Whitcher, Naveed Sattar, Jimmy D Bell, E Louise Thomas, Madeleine Cule, Hanieh Yaghootkar.

We aimed to identify distinct axes of obesity using advanced MRI-derived phenotypes. We used 24 MRI-derived fat distribution and muscle volume measures (UK Biobank, n= 33,122) to construct obesity axes through principal component analysis (PCA). Genome-wide association studies were performed for each axis to uncover genetic factors, followed by pathway enrichment, genetic correlation, and Mendelian randomization analyses to investigate disease associations. Four primary obesity axes were identified: (1) General Obesity, reflecting higher fat accumulation in all regions (visceral, subcutaneous, and ectopic fat); (2) Muscle-Dominant, indicating greater muscle volume; (3) Peripheral Fat, associated with higher subcutaneous fat in abdominal and thigh regions; and (4) Lower Body Fat, characterized by increased lower-body subcutaneous fat and reduced ectopic fat. Each axis was associated with distinct genetic loci and pathways. For instance, the Lower Body Fat Axis was associated with RSPO3 and COBLL1 which are emerging as promising candidates for therapeutic targeting. Disease risks varied across axes: the General Obesity Axis correlated with higher risks of metabolic and cardiovascular diseases; the Lower Body Fat Axis appeared protective against type 2 diabetes and cardiovascular disease. This study highlights the heterogeneity of obesity through the identification of obesity axes and emphasizes the potential to extend beyond BMI in defining and treating obesity for obesity-related disease management.

DOI: https://doi.org/10.2337/db24-1103