bims-mimead 2025-07-27 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–07–27
eight papers selected by
Rachel M. Handy, University of Guelph

Obesity duration is linked to bariatric surgery outcomes via adipose tissue response.
Metformin Suppresses the Mitochondrial and Transcriptional Response to Exercise Revealing a Conserved BCL6B Associated Angiogenic Program.
Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues.
Exercise training remodels inter-organ endocrine networks.
Deletion of EP3 prostaglandin receptor in murine macrophages aggravates diet-induced obesity by suppressing SPARC.
The effect of amycretin, a unimolecular glucagon-like peptide-1 and amylin receptor agonist, on body weight and metabolic dysfunction in mice and rats.
Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer.
Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis.

J Endocrinol. 2025 Jul 23. pii: JOE-25-0013. [Epub ahead of print]

Obesity duration is linked to bariatric surgery outcomes via adipose tissue response.

Julia Sánchez-Ceinos, Bethan C Townsend, Carmen Tercero-Alcázar, Jaime López-Alcalá, Ignacio Ortea, Salvador Morales-Conde, José L Pereira-Cunill, Pedro P García-Luna, David A Cano, María M Malagón, Rocío Guzmán-Ruiz.

  Bariatric surgery (BS) is the most effective treatment for obesity and its related comorbidities, resulting in significant adipose tissue (AT) loss and functional recovery. However, the molecular mechanisms in the AT that drive these health benefits remain poorly understood, and predictive factors for adequate weight loss are currently needed. This study aimed to identify the proteomic signature of subcutaneous AT (SAT) linked to BS-induced weight loss and metabolic improvement, and to determine potential predictors of individual response. Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) proteomics was performed on paired abdominal SAT samples from individuals with obesity before and after BS. Bioinformatic and correlation analyses were conducted between proteomic data and changes in anthropometric and clinical parameters. Additionally, the effect of sera from BS participants on subcutaneous adipocytes was assessed in vitro. The SAT response to BS was characterized by an up-regulation of mitochondrial metabolism and a down-regulation of inflammation, which correlated with different anthropometric and circulating markers. Notably, obesity duration was associated with BS-induced weight loss. Individuals with short-standing obesity (SSO) exhibited greater proteomic remodelling, weight reduction, and clinical improvement post-BS than those with long-standing obesity (LSO). Furthermore, a regulatory axis involving miR-223-3p, glucose metabolism, and cytoskeleton reorganization in adipocytes might be connected to the positive effects of BS in LSO. Overall, our results indicate that obesity duration is related to BS-induced weight loss through SAT proteomic remodeling. Addressing this relationship could help develop new strategies to enhance weight management and metabolic health in people living with obesity.

Keywords:  adipose tissue; bariatric surgery; obesity duration; proteomics

DOI:  https://doi.org/10.1530/JOE-25-0013
J Appl Physiol (1985). 2025 Jul 22.

Metformin Suppresses the Mitochondrial and Transcriptional Response to Exercise Revealing a Conserved BCL6B Associated Angiogenic Program.

Matthew D Bruss, Christian James Elliehausen, Josef P Clark, Dennis M Minton, Adam R Konopka.

  We have previously demonstrated that the inhibitory effect of metformin on skeletal muscle mitochondrial respiration was associated with attenuated improvements in whole-body insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) in older adults. To identify processes associated with the inhibitory effect of metformin on mitochondrial adaptations to AET, we evaluated the skeletal muscle transcriptome, mitochondrial respiration, and hydrogen peroxide (H2O2) emissions in 7-month-old male C57BL6/J mice after 8-weeks of non-exercise sedentary control (SED) or progressive AET with and without metformin treatment. Similar to our findings in humans, metformin diminished the improvement in whole-body cardiometabolic adaptations and the increase in mitochondrial respiration in both isolated mitochondria and permeabilized muscle fibers after AET in mice. However, AET with or without metformin did not impact resting mitochondrial H2O2 emissions. Metformin decreased the number of differentially expressed genes after AET by ~50% and suppressed several transcription factors and signal transduction pathways involved in skeletal muscle proteostasis, myogenesis, oxidative capacity, and angiogenesis. A parallel analysis of human resistance exercise data revealed overlapping metformin-sensitive transcription factors and BCL6B-associated signaling networks implicated in angiogenesis, suggesting a conserved regulatory axis across species and exercise modalities. Collectively, these data demonstrate that attenuation of mitochondrial respiration by metformin coincides with transcriptional repression and identify specific pathways and regulators, such as BCL6B, that may contribute to the suppression of exercise adaptations by metformin.

Keywords:  BCL6B; PI3K-AKT-mTOR; angiogenesis; endurance exercise; respiration

DOI:  https://doi.org/10.1152/japplphysiol.00432.2025
Cell Genom. 2025 Jul 16. pii: S2666-979X(25)00207-1. [Epub ahead of print] 100951

Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues.

Wenjing Wang, Wei Lin Liew, Shiqi Huang, Edmund Chan, Amelia Li Min Tan, Chi Tian, Yihan Tong, Yuntian Zhang, Fei Liu, Yixian Qin, Sean Jun Leong Ou, Suresh Anand Sadananthan, Sambasivam Sendhil Velan, Kavita Venkataraman, Sarah R Langley, Petretto Enrico, Shawn Hoon, Kwang Wei Tham, Yap Seng Chong, Yung Seng Lee, Melvin Khee-Shing Leow, Xueling Sim, Chin Meng Khoo, E Shyong Tai, Eric Yin Hao Khoo, Mei Hui Liu, Boxiang Liu.

  Weight loss through exercise and diet reduces the risk of type 2 diabetes, but the genetic regulation of gene expression and splicing in response to weight loss remains unclear in humans. We collected clinical data and skeletal muscle biopsies from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention, which resulted in an average of ∼10% weight loss, accompanied by an ∼30% increase in insulin-stimulated glucose uptake. Improvements were observed in 118 of 252 clinical traits and six blood lipids. Transcriptomic analysis of paired skeletal muscle biopsies identified 505 differentially expressed genes enriched in mitochondrial function and insulin sensitivity. Thousands of muscle-specific expression/splicing quantitative trait loci (e/sQTLs) were detected pre- and post-intervention, including hundreds of lifestyle-responsive e/sQTLs. Notably, approximately 4.2% of eQTLs and 7.3% of sQTLs showed Asian specificity. Joint analysis with genome-wide association study (GWAS) identified 16 putative metabolic risk genes. Our study reveals gene-by-lifestyle interactions and how lifestyle modulates gene regulation in skeletal muscle.

Keywords:  Asian-specific QTL; gene-by-lifestyle interaction; human intervention study; lifestyle modifications; metabolic disease; skeletal muscle transcriptomics; weight loss

DOI:  https://doi.org/10.1016/j.xgen.2025.100951
Mol Metab. 2025 Jul 21. pii: S2212-8778(25)00126-7. [Epub ahead of print] 102219

Exercise training remodels inter-organ endocrine networks.

Cheehoon Ahn, Andrea L Hevener, Laurie J Goodyear, Sue C Bodine, Karyn A Esser, Marcus M Seldin, Lauren M Sparks.

Exercise induces organism-wide molecular adaptations, partly mediated by humoral factors released in response to acute and chronic physical activity. However, the extent and specificity of endocrine effects from training-induced secreted factors remain unclear. Here, we applied systems genetics approaches to quantify inter-organ endocrine networks using multi-tissue transcriptomics and proteomics data collected from endurance-trained rats in The Molecular Transducers of Physical Activity Consortium (MoTrPAC). Eight weeks of endurance training significantly altered both the magnitude and specificity of endocrine effects across multiple origin-target tissue pairs. Subcutaneous white adipose tissue emerged as a key endocrine regulator impacted by training, while extracellular matrix-derived factors were identified as globally regulated secretory features in trained vs sedentary animals. Notably, secretory Wnt signaling factors were identified as key mediators of exercise-induced endocrine adaptations in multiple tissues. Our systems genetics framework provides an unprecedented atlas of inter-organ communication significantly remodeled by endurance exercise, serving as a valuable resource for novel exerkine discovery.

DOI: https://doi.org/10.1016/j.molmet.2025.102219
EMBO J. 2025 Jul 23.

Deletion of EP3 prostaglandin receptor in murine macrophages aggravates diet-induced obesity by suppressing SPARC.

Wenlong Shang, Yinxiu Li, Lu Wang, Jiao Liu, Huiwen Ren, Qian Liu, Shumin Guo, Yuhong Wang, Yubo Ma, Tianyi You, Yujun Shen, Yu Zhou, Danyang Tian, Ying Yu.

  Macrophages are primary immune cells involved in obesity-triggered chronic low-grade inflammation in adipose tissues. Prostaglandin E2 (PGE2), mainly generated from macrophages, can regulate adipose tissue remodeling, yet the underlying mechanisms are not fully understood. Here, we observed that PGE2 receptor subtype 3 (EP3) was remarkably downregulated in adipose tissue macrophages from high-fat diet (HFD)-fed mice and patients with obesity. Notably, macrophage-specific deletion of EP3 exacerbated HFD-induced fat expansion, whereas EP3α isoform overexpression in macrophages alleviated obesity phenotypes. Further, EP3 deficiency suppressed secretion of anti-adipogenic matricellular protein SPARC from macrophages. SPARC deletion in macrophages abrogated the protection of EP3-overexpression against diet-induced obesity. Mechanistically, EP3 activation promoted SPARC expression by suppressing DNA methylation in macrophages through a PKA-Sp1-Dnmt1/3a signaling cascade. Finally, EP3 agonist treatment ameliorated HFD-induced obesity in mice. Thus, EP3 inhibits adipogenesis through promoting release of SPARC from macrophages, suggesting a novel therapeutic target for diet-induced obesity.

Keywords:  E-prostanoid 3 Receptor; Macrophage; Obesity; SPARC

DOI:  https://doi.org/10.1038/s44318-025-00508-y
EBioMedicine. 2025 Jul 23. pii: S2352-3964(25)00306-8. [Epub ahead of print]118 105862

The effect of amycretin, a unimolecular glucagon-like peptide-1 and amylin receptor agonist, on body weight and metabolic dysfunction in mice and rats.

Rune Ehrenreich Kuhre, Borja Ballarín-González, Christian Lehn Brand, Tine Glendorf, Kim Grimstrup Madsen, Karina Rahr Hjøllund, Wouter Frederik Johan Hogendorf, David Højland Ipsen, Sofia Lundh, Thomas Kruse, Signe Beck Petersen, Anna Secher, Andreas Vegge, Kirsten Raun.

   BACKGROUND: Amycretin is a novel unimolecular glucagon-like peptide-1 (GLP-1) and amylin receptor agonist. This study aimed to determine its role in mitigating diet-induced metabolic disorders, such as obesity, insulin resistance, and fatty liver disease, in mice and rats.
METHODS: Preclinical studies were conducted to characterise amycretin activation of GLP-1, amylin and calcitonin receptors, and determine the effects of amycretin administration on the metabolic health of mice and rats. Investigations included measurements of body weight and body composition, energy intake and energy expenditure, insulin sensitivity, metabolic dysfunction-associated steatotic liver disease (MASLD), and access in the mouse brain.
FINDINGS: Amycretin activated human, mouse and rat GLP-1, amylin and calcitonin receptors in cell-based systems. In diet-induced obese (DIO) rats, amycretin administration for 21 days reduced total energy intake by 47% (95% CI (mean), kcal: vehicle: 2132-2493 vs. amycretin: 1044-1390) and lowered body weight by 18% (95% CI (mean), % change relative to pre-treatment: vehicle: 6.56-8.47 vs. amycretin: -10.48 to -12.74, p < 0.0001), while maintaining energy expenditure. Amycretin targeted key areas of the mouse brain that regulate food intake. Insulin sensitivity improved significantly with amycretin administration in DIO rats compared with vehicle controls, shown by higher glucose infusion rates during a hyperinsulinaemic euglycemic clamp. Additionally, amycretin improved histological hallmarks of MASLD, primarily by reducing steatosis.
INTERPRETATION: Amycretin had various beneficial effects on metabolic health in mice and rats; effectively reducing body weight, enhancing insulin sensitivity, and improving MASLD activity scores. Thus, amycretin could be a promising therapeutic option for metabolic diseases including obesity and type 2 diabetes, warranting further clinical trials assessing its efficacy in humans.
FUNDING: Novo Nordisk A/S.

Keywords:  Amylin receptor; Glucagon-like peptide-1 receptor; Metabolism; Obesity

DOI:  https://doi.org/10.1016/j.ebiom.2025.105862
Mol Metab. 2025 Jul 16. pii: S2212-8778(25)00118-8. [Epub ahead of print] 102211

Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer.

Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Luke D Flewwelling, Nathaniel J Andrews, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Leslie Ogilvie, Stavroula Tsitkanou, Jeremy A Simpson, Nicholas P Greene, Arthur J Cheng, Jim Petrik, Christopher G R Perry.

  Muscle loss with cancer causes weakness, worsens quality of life, and predicts reduced overall survival rates. Recently, muscle weakness was identified during early-stage cancer before atrophy develops. This discovery indicates that mechanisms independent of muscle loss must contribute to progressive weakness. While mitochondrial stress responses are associated with early-stage 'pre-cachexia' weakness, a causal relationship has not been established. Here, using a mouse model of metastatic ovarian cancer cachexia, we identified that the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents muscle weakness occurring before the development of atrophy in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. These findings indicate that atrophy-independent mechanisms of muscle weakness occur in different muscle types throughout ovarian cancer. Ovarian cancer reduced flexor digitorum brevis (FDB) whole muscle force production and myoplasmic free calcium ([Ca2+]i) during contraction in intact single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout ovarian cancer. These discoveries identify that muscle weakness can occur independent of atrophy throughout ovarian cancer in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force early during ovarian cancer during the pre-atrophy period and in late stages once cachexia has become severe.

Keywords:  Ovarian cancer cachexia; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2025.102211
Nat Med. 2025 Jul 21.

Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis.

Maximilian Jara, Jenny Norlin, Mette Skalshøi Kjær, Kasper Almholt, Kristian M Bendtsen, Elisabetta Bugianesi, Kenneth Cusi, Elisabeth D Galsgaard, Milan Geybels, Lise L Gluud, Lea M Harder, Rohit Loomba, Gianluca Mazzoni, Philip N Newsome, Louise M Nitze, Mads S Palle, Vlad Ratziu, Anne-Sophie Sejling, Vincent W-S Wong, Quentin M Anstee, Lotte B Knudsen.

Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. Here we show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation and reduced hepatic expression of fibrosis-related and inflammation-related gene pathways. Aptamer-based proteomic analyses of serum samples from patients with MASH in a clinical trial identified 72 proteins significantly associated with MASH resolution and semaglutide treatment, with most related to metabolism and several implicated in fibrosis and inflammation. An independent real-world cohort verified the pathophysiological relevance of this signature, showing that the same 72 proteins are differentially expressed in patients with MASH relative to healthy individuals. Taken together, these data suggest that semaglutide may revert the circulating proteome associated with MASH to the proteomic pattern observed in healthy individuals.

DOI: https://doi.org/10.1038/s41591-025-03799-0