bims-mimead 2025-11-23 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–11–23
ten papers selected by
Rachel M. Handy, University of Guelph

Induction of yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice.
Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice.
Myokine IL-6 activity enhances post-exercise fatty acid accumulation in skeletal muscle but does not affect glycogen resynthesis.
Deletion of fibro-adipogenic progenitors-specific follistatin impairs muscle function and accelerates skeletal muscle atrophy in obese mice.
Subcutaneous white adipose tissue-derived extracellular vesicles maintain intestinal homeostasis via IgA biosynthesis in aging mice.
Daily Myofibrillar Protein Synthesis Rates Do Not Differ During Interval Compared to Continuous Exercise Training Matched for Duration and Work in Healthy Young Men.
Gut microbiome-adipose crosstalk modulates soluble IL-6 receptor influencing exercise responsiveness in glycemic control and insulin sensitivity.
Isolating the effects of carbohydrate and lipid availability on exercise-induced skeletal muscle signalling in males.
Alpha-linolenic acid regulates white adipose tissue lipolysis independent of background dietary protein.
Blood and adipose tissue DNA methylation in adults born preterm with a very low birth weight - a sibling comparison study.

Metabolism. 2025 Nov 18. pii: S0026-0495(25)00308-7. [Epub ahead of print] 156439

Induction of yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice.

Line Pedersen, Christy M Gliniak, Thomas Myhre Dale, Qingzhang Zhu, Chao Li, Jan-Bernd Funcke, Clair Crewe, Jiahui Luo, Lauren Palluth, Yi Zhu, Philipp E Scherer.

  The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of Yy1 in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.

Keywords:  Adipogenesis; Adipose tissue; Obesity; White adipose tissue; YY1

DOI:  https://doi.org/10.1016/j.metabol.2025.156439
bioRxiv. 2025 Oct 02. pii: 2025.09.30.679563. [Epub ahead of print]

Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice.

Daniel Ferguson, Elise I Gadson, Kathleen R Markan, Jun Yoshino, Maxwell Lin, Mohammad Habibi, Snigdha Tiash, Xiaoxia Cui, Evguenia Kouranova, Edziu Franczak, Qiuyuan Guo, Jill Kealing, Terri A Pietka, Kim H H Liss, John P Thyfault, Gary J Patti, Brian N Finck, Clair Crewe, Sandip Mukherjee.

Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme and a central factor in energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) maintains the cellular NAD+ pool by synthesizing the NAD+ precursor, nicotinamide mononucleotide (NMN), and diminished adipocyte NAMPT activity has been implicated in aging- and obesity-related metabolic dysfunction. Herein, we examined the effects of overexpressing or knocking out NAMPT in adipocytes on metabolic dysfunction and interorgan communication in mice. We generated new adipocyte-specific NAMPT overexpressing( ANOV ) mice model. Male ANOV mice are protected from diet-induced metabolic dysfunction including adipose tissue inflammation, glucose intolerance, and insulin resistance. In contrast female ANOV mice were less protected from metabolic dysfunction, possibly due to higher endogenous expression of NAMPT in WT female mice. Livers of ANOV mice showed improved insulin signaling, increased NAD content, and reduced steatosis, suggesting that NAMPT regulates interorgan communication between adipocytes and hepatocytes. Extracellular vesicles (EV) isolated from ANOV mice enhanced insulin signaling in HepG2 cells and improved glucose tolerance in WT obese mice. In contrast, EV from ANKO mice suppressed HepG2 insulin signaling and inhibition of EV release improved glucose tolerance in ANKO female mice. Collectively, these data highlight a novel mechanism by which adipocyte NAD+ metabolism regulates systemic metabolic dysfunction via EVs.

DOI: https://doi.org/10.1101/2025.09.30.679563
Mol Metab. 2025 Nov 14. pii: S2212-8778(25)00190-5. [Epub ahead of print] 102283

Myokine IL-6 activity enhances post-exercise fatty acid accumulation in skeletal muscle but does not affect glycogen resynthesis.

Timothy M Kistner, Beckey Trinh, Karl Mfeketo, Gerrit Van-Hall, Bente K Pedersen, Daniel E Lieberman, Helga Ellingsgaard.

  During exercise, myokine interleukin 6 (IL-6) plays a variety of metabolic roles including acting as a muscular energy sensor and liberating somatic energy stores. While the effects of IL-6 are relatively well-defined during exercise, its role in muscular metabolism during exercise recovery in humans has not been addressed. To test whether myokine IL-6 allocates fat and glucose towards muscle, we conducted a randomized double-blind trial with 30 men (Age: 25.2 ± 3 yrs. BMI: 23.0 ± 1.5 kg/m2) where participants exercised at a moderate intensity for two hours and received either tocilizumab to block IL-6 activity, or placebo. Continuous infusions of isotopically labeled palmitate, glucose, and glycerol paired with blood, breath, and muscle samples were used to measure muscle-specific metabolism. IL-6 blockade did not affect exercise performance, substrate utilization, or glucose, fatty acid and glycerol kinetics during exercise. During recovery, IL-6 blockade decreased the appearance of oral glucose and lowered the insulin response to a glucose drink. Despite this difference in glucose and insulin, the rate of post-exercise glycogen resynthesis before and after the ingestion of glucose was not altered between groups. Although IL-6 blockade did not affect lipolysis during exercise, it attenuated the accumulation of esterified oleate in muscle during recovery before the glucose drink was given. Furthermore, IL-6 blockade attenuated IL-1RA production in recovery but did not alter IL-10 secretion. Together, these results imply that during recovery from moderate-intensity exercise, myokine IL-6 primarily regulates fatty acid metabolism within muscle and leaves glucose metabolism largely unaffected. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT05349149).

Keywords:  energy metabolism; exercise; interleukin-6; lipid metabolism; myokines; recovery; tocilizumab

DOI:  https://doi.org/10.1016/j.molmet.2025.102283
Mol Med. 2025 Nov 21.

Deletion of fibro-adipogenic progenitors-specific follistatin impairs muscle function and accelerates skeletal muscle atrophy in obese mice.

Muhammad Rahil Aslam, Muhammad Bilal, Allah Nawaz, Tomonobu Kado, Shinya Abe, Nguyen Quynh Phuong, Memoona, Sana Khalid, Le Duc Anh, Ayumi Nishimura, Yoshiyuki Watanabe, Yoshiko Igarashi, Naeem Iqbal, Maki Yokoyama, Yasuhiro Onogi, Kennichi Hirabayashi, Hiroyuki Miwa, Takumi Era, Martin M Matzuk, Seiji Yamamoto, Koichi Ikuta, Isao Usui, Kohta Kobayashi, Toshihiko Satake, Masaru Kato, Shiho Fujisaka, Kazuyuki Tobe.

   BACKGROUND: Follistatin is a potent regulator of various TGF-β superfamily members, including myostatin (MSTN) and activin A. Previous studies have shown that follistatin is crucial in enhancing myogenesis during acute muscle injury. The mechanism by which fibro-adipogenic progenitors (FAPs)-specific follistatin influences muscle homeostasis in obese mice remains unknown. Therefore, we investigated the physiological role of follistatin in PDGFRα-positive FAPs in the regulation of muscle homeostasis and exercise in obese mice.
METHODS: A PDGFRα-specific follistatin knockout (follistatin KO) mouse model was generated using PDGFRα-GFP-CreERT2 (PDGFRα-GCE) and follistatinflox/flox mice. These mice were fed a 60% high-fat diet (HFD) for 20 weeks, followed by a series of analyses, including exercise tolerance test, grip strength test, glucose and insulin tolerance assays, gene expression analysis, histology, western blotting, and immunohistochemistry.
RESULTS: We showed that follistatin KO mice had reduced expression of Fst in skeletal muscle and white adipose tissue. We also showed that follistatin KO mice exhibited decreased exercise performance and altered skeletal homeostasis during obesity. Deletion of follistatin in FAPs activated the MSTN: Activin A/SMADs signaling pathways, which negatively impacted muscle homeostasis. Furthermore, follistatin KO mice showed reduced muscle mass, increased muscle degradation, and atrophic myofibers. Mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation were also altered in the skeletal muscles of follistatin KO mice.
CONCLUSION: Follistatin plays a protective role in mice by maintaining the metabolic health of skeletal muscles; it restores muscle function during HFD challenge, thereby reducing diet-induced obesity-related complications.

Keywords:  Exercise capacity; Fibro-adipogenic progenitors (FAPs); Follistatin; Muscle mass; Obesity

DOI:  https://doi.org/10.1186/s10020-025-01393-1
J Clin Invest. 2025 Nov 17. pii: e188947. [Epub ahead of print]135(22):

Subcutaneous white adipose tissue-derived extracellular vesicles maintain intestinal homeostasis via IgA biosynthesis in aging mice.

KeKao Long, Pujie Liu, Yi Wang, Jordy Evan Sulaiman, Moinul Hoque, Gloria Hoi Yee Li, Daisy Danyue Zhao, Pui-Kei Lee, Gilman Kit-Hang Siu, Annie Wing-Tung Lee, Zhuohao Liu, Pui-Kin So, Yin Cai, Connie Wai-Hong Woo, Chi-Bun Chan, Aimin Xu, Kenneth King-Yip Cheng.

  Intestinal function and white adipose tissue (WAT) function deteriorate with age, but whether and how their deterioration is intertwined remains unknown. Increased gut permeability, microbiota dysbiosis, and aberrant immune microenvironment are the hallmarks of intestinal dysfunctions in aging. Here, we show that subcutaneous WAT dysfunction triggered aging-like intestinal dysfunctions in mouse models. Removal of inguinal subcutaneous WAT (iWAT) increased intestinal permeability and inflammation and altered gut microbiota composition as well as susceptibility to pathogen infection in mouse models. These intestinal dysfunctions were accompanied by a reduction of immunoglobulin A-producing (IgA-producing) cells and IgA biosynthesis in the lamina propria of the small intestine. Retinoic acid (RA) is a key cargo within iWAT-derived extracellular vesicles (iWAT-EVs), which, at least in part, elicits IgA class-switching and production in the small intestine and maintains microbiota homeostasis. RA content in iWAT-EVs and intestinal IgA biosynthesis are reduced during aging in mice. Replenishment of "young" iWAT-EVs rejuvenates intestinal IgA production machinery and shifts microbiota composition of aged mice to a "youth" status, which alleviates leaky gut via RA. In conclusion, our findings suggest that iWAT-EVs with RA orchestrate IgA-mediated gut microbiota homeostasis by acting on intestinal B cells, thereby maintaining intestinal health during aging.

Keywords:  Adipose tissue; Aging; B cells; Endocrinology; Immunoglobulins; Immunology

DOI:  https://doi.org/10.1172/JCI188947
Int J Sport Nutr Exerc Metab. 2025 Nov 20. 1-8

Daily Myofibrillar Protein Synthesis Rates Do Not Differ During Interval Compared to Continuous Exercise Training Matched for Duration and Work in Healthy Young Men.

Jorn Trommelen, Martin J MacInnis, Joshua P Nederveen, Jean Nyakayiru, Bryon R McKay, Sara Y Oikawa, Joy P B Goessens, Dinesh Kumbhare, Gianni Parise, Stuart M Phillips, Martin J Gibala, Luc J C van Loon.

  High-intensity interval training (HIIT) may elicit different skeletal muscle responses compared to work-matched moderate-intensity continuous training (MICT). The effect of work-matched HIIT versus MICT on myofibrillar protein synthesis remains to be determined. In the present study, we assessed the effect of short-term HIIT versus MICT on myofibrillar protein synthesis rates using a single-leg within-participant design. Ten healthy young men (age: 20 ± 1 years) performed six to eight training sessions with each leg over 2 weeks while ingesting deuterated water to assess myofibrillar protein synthesis. One leg was randomly assigned to perform HIIT and the other MICT. Skeletal muscle biopsies were collected at rest from one leg before and after a 2-week habituation period and from both legs after the training period to assess myofibrillar protein synthesis rates. HIIT and MICT increased single-leg maximal power output (main effect, p < .01), with no differences between legs (interaction: p = .61). Myofibrillar protein synthesis rates did not differ between the habituation period, MICT, or HIIT (1.39 ± 0.16%, 1.24 ± 0.30%, and 1.42 ± 0.31% per day, respectively; p = .29). In conclusion, we observed no detectable differences in daily myofibrillar protein synthesis rates between HIIT or work-matched MICT when assessed over a 2-week exercise training period in recreationally active young adult men.

Keywords:  aerobic exercise; deuterated water; exercise intensity; heavy water; muscle protein synthesis

DOI:  https://doi.org/10.1123/ijsnem.2025-0074
Cell Metab. 2025 Nov 18. pii: S1550-4131(25)00473-5. [Epub ahead of print]

Gut microbiome-adipose crosstalk modulates soluble IL-6 receptor influencing exercise responsiveness in glycemic control and insulin sensitivity.

Yao Wang, Jiaming Wu, Jianyu Yao, Jiarui Chen, Kenneth K Y Cheng, Melody Yuen-Man Ho, Chi Ho Lee, Karen Siu-Ling Lam, Michael Andrew Tse, Gianni Panagiotou, Aimin Xu.

  Exercise is an effective intervention for the prevention and management of diabetes, but the high interpersonal variability in response to exercise impedes its widespread implementation. Herein, we identify adipocyte-derived soluble interleukin-6 receptor (sIL-6R) as a key exerkine determining exercise efficacy in improving metabolic health. In individuals with obesity who underwent a 12-week exercise intervention, circulating sIL-6R level exhibits dichotomous changes between exercise responders (Rs) and non-responders (NRs), in close association with exercise-mediated alterations in insulin sensitivity and glycemic control. Mechanistically, elevated gut microbiome-mediated leucine in NR acts on white adipocytes to promote disintegrin and metalloproteinase 17 (ADAM17)-mediated sIL-6R production via the mammalian target of rapamycin (mTOR)-hypoxia-inducible factor 1α (HIF1α) pathway, which in turn impairs the metabolic benefits of exercise through interleukin (IL)-6 trans-signaling-induced adipose inflammation. Adipocyte-selective ablation of ADAM17 prevents the effects of fecal microbiota transplantation from NR on elevation of sIL-6R, thereby restoring the efficacy of exercise-shaped gut microbiome in counteracting glucose intolerance and insulin resistance in obese mice. Thus, therapeutic interventions targeting adipocyte-derived sIL-6R represent a promising strategy for maximizing exercise efficacy in personalized diabetes prevention.

Keywords:  ADAM17; IL-6 signaling; adipokines; adipose inflammation; diabetes prevention; exercise interventions; exerkines; gut-adipose tissue crosstalk; insulin resistance; leucine

DOI:  https://doi.org/10.1016/j.cmet.2025.10.013
J Physiol. 2025 Nov 16.

Isolating the effects of carbohydrate and lipid availability on exercise-induced skeletal muscle signalling in males.

Louise Bradshaw, Alfonso Moreno Cabañas, Bruno Spellanzon, Katie Marie Hutchins, Adam J Collins, Jariya Buniam, Thibaux van der Stede, Joanne Mallinson, Kostas Tsintzas, Wim Derave, Jean-Philippe Walhin, James A Betts, Francoise Koumanov, Javier T Gonzalez.

  Training with low carbohydrate availability can increase AMP-activated protein kinase (AMPK) activation, but whether increased AMPK activation is the result of low carbohydrate availability per se or concurrent increases in fatty acid availability/oxidation is unclear. This study assessed the independent effects of carbohydrate and fatty acid availability on exercise-induced skeletal muscle AMPK activation and downstream signalling. Eight active males who were aged between 18 and 60 years with a body mass index in the range 18.0-30.0 kg m-2 cycled on three occasions for 60 min at 95% of lactate threshold 1 with ingestion of either carbohydrate (CARB), niacin (NIACIN) or placebo (FAST) in a crossover design (11 ± 6 days washout). Blood and exhaled breath were sampled throughout exercise and muscle was sampled pre- and post-exercise. Fat oxidation and plasma non-esterified fatty acid concentrations were both lower in CARB vs. FAST with negligible difference between CARB vs. NIACIN. Plasma insulin concentrations were higher in CARB compared with both FAST and NIACIN. Net muscle glycogen use was greater with NIACIN vs. CARB. Although no evidence for differences were observed for phosphorylated AMPK, the downstream target, phosphorylated acetyl-CoA carboxylase was decreased with CARB vs. both FAST (-0.7 ± 0.6 fold, P = 0.04) and NIACIN (-1.0 ± 0.8 fold, P = 0.02). RNA-sequencing displayed several canonical changes with exercise but little difference between conditions. These data suggest carbohydrate ingestion suppresses exercise-induced phosphorylation of acetyl-CoA carboxylase independent of fatty acid availability. KEY POINTS: It is currently unknown whether the enhanced physiological adaptation to regularly exercising in a fasted-state are explained by low carbohydrate availability and/or the concomitant increase in fatty acid availability. This study used fasted exercise with niacin ingestion to reduce the lipaemic response associated with fasted exercise to isolate the effects of carbohydrate vs. fatty acid availability on exercise-induced skeletal muscle signalling. Our data show niacin ingestion increases muscle glycogen utilisation compared to carbohydrate ingestion during exercise, but both niacin and carbohydrate ingestion suppress fatty acid availability and fat oxidation to a similar extent. Our data demonstrate carbohydrate ingestion during exercise suppresses acetyl-CoA carboxylase phosphorylation compared to both niacin ingestion and extended overnight fasting. These data suggest that high carbohydrate availability inhibits exercise-induced acetyl-CoA carboxylase phosphorylation in human skeletal muscle, independent of circulating fatty acid concentrations.

Keywords:  carbohydrate metabolism; cell signalling; exercise metabolism; lipid metabolism

DOI:  https://doi.org/10.1113/JP289864
J Nutr Biochem. 2025 Nov 13. pii: S0955-2863(25)00347-X. [Epub ahead of print] 110185

Alpha-linolenic acid regulates white adipose tissue lipolysis independent of background dietary protein.

Siobhan E Woods, Melissa Gonzalez-Soto, Alexa N King, Frédéric Capel, David C Wright, David M Mutch.

  White adipose tissue (WAT) is an endocrine organ essential for maintaining whole-body energy balance by regulating fatty acid uptake, storage, and release. Emerging evidence indicates that omega-3 fatty acids have a role in modulating WAT lipid metabolism. While most studies have focused on marine-derived omega-3s, considerably less is known about alpha-linolenic acid (ALA). Previous research suggests that ALA may prevent or restore impaired lipolysis in dysfunctional WAT. The primary objective of this study was to examine the effects of ALA on WAT lipolytic activity and whether this varied with background dietary protein. Male C57BL/6N mice (n=16/group) were fed moderate-fat diets containing either 1% (low-ALA) or 3% (high-ALA) energy from ALA (provided by flaxseed oil), and either skim milk protein or a soy protein isolate for 8 weeks. Mice fed high-ALA diets showed increased body weight gain and WAT depot weights, reduced serum triglycerides, and increased serum glycerol levels. The higher serum glycerol levels in high-ALA fed mice were reflected in higher glycerol release from cultured adipose tissue explants stimulated with a β-adrenergic agonist. Markers of WAT lipolysis, including ATGL and phosphorylated HSL, were either lower or unchanged in mice fed high-ALA diets. Background dietary protein (from either dairy or soy) had little-to-no-effect on study endpoints. Our data suggests that increased dietary ALA intake improves circulating TAG levels while reducing markers of lipolysis in WAT depots. The increase in glycerol observed with high-ALA intake may point to a potential regulation of WAT glycerogenesis and/or aquaporin expression that warrants future investigation.

Keywords:  ALA; adipose tissue; dairy; lipolysis; mouse; omega-3 fatty acids; soy

DOI:  https://doi.org/10.1016/j.jnutbio.2025.110185
Epigenomics. 2025 Nov 17. 1-14

Blood and adipose tissue DNA methylation in adults born preterm with a very low birth weight - a sibling comparison study.

Helena H Hauta-Alus, Justiina Ronkainen, Juho Kuula, Darina Czamara, Anni Heiskala, Samuel Sandboge, Johan Björkqvist, Nina Kaseva, Katri Räikkönen, Kirsi H Pietiläinen, Sylvain Sebert, Eero Kajantie.

   BACKGROUND: Preterm birth and very low birth weight (VLBW; <1500 g) increase risks for poor health outcomes, potentially mediated by epigenetic modifications such as DNA methylation (DNAm). We hypothesized that DNAm differs between VLBW adults and their siblings in blood and adipose tissue.
METHODS: We studied 75 adults born preterm with VLBW and 73 same-sex sibling controls from the Adults Born Preterm Sibling Study. DNAm at cytosine-guanine dinucleotide (CpG) sites in blood and adipose tissue was assessed using Illumina EPIC 850K at a mean age of 29 years. Biological pathways were investigated with QIAGEN ingenuity pathway analysis (IPA).
RESULTS: No differences were observed in blood DNAm. In adipose tissue, 458 CpG sites were differentially methylated (FDR p < 0.05) between VLBW and siblings. Top sites were annotated to genes related to lipid metabolism (cg00264176 (FADS2), 0.077 (0.007), FDR p = 3.24 × 10-14) and neural development (cg08277679 (KIF26A), 0.053 (0.005), FDR p = 8.22 × 10-12). IPA identified enrichment for 81 pathways (FDR p < 0.05).
CONCLUSION: Our results suggest tissue-specific DNAm differences in VLBW adults compared to their siblings. The changes cluster in pathways related to lipid metabolism, neurodevelopment, and cardiometabolic regulation, suggesting lasting tissue-specific epigenetic modifications in VLBW adults.

Keywords:  DNA methylation; Epigenome-wide association studies (EWAS); adipose tissue; preterm birth; very low birth weight (VLBW)

DOI:  https://doi.org/10.1080/17501911.2025.2583893