bims-mimead 2026-07-12 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2026–07–12
seven papers selected by
Rachel M. Handy, University of Guelph and Universiteit Mastricht

A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.
Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice via Extracellular Vesicles.
Endurance Exercise Elicits a Hepatic Memory Associated with Improved Metabolic Function and Protein Secretion.
Divergent AKT Signalling Mechanisms Regulate GLUT4 Translocation and Glucose Uptake in Skeletal Muscle and Adipose Tissue.
Fasting-induced glucose intolerance is not impacted by the addition of daily exercise: A randomized crossover study.
Skeletal muscle biomass as an underappreciated fate of glucose.
Bridging the gap: Multi-omic Insights into Exercise Responses in Post-Menopausal Women.

Cell Rep. 2026 Jul 04. pii: S2211-1247(26)00681-9. [Epub ahead of print]45(7): 117603

A cold-induced GDF15-secreting adipocyte subpopulation regulates energy homeostasis through endocrine signaling.

Chunyan Wu, Tongtong Wang, Songlin Gong, Jing Zhang, Charlotte G Mann, Min Li, Ziyu Liu, Yizhi Sun, Shenwei Shi, Zhenghong Liu, Katrien De Bock, Miroslav Balaz, John Speakman, Christian Wolfrum.

  Brown adipose tissue (BAT) regulates whole-body energy balance through uncoupling protein 1 (UCP1)-dependent thermogenesis and secretion of metabolic factors. Recent studies suggest UCP1-independent mechanisms contribute to energy balance, with UCP1 being conditionally dispensable. However, how adaptation to UCP1 deficiency is regulated remains unclear. Our single-nucleus RNA sequencing of BAT from cold-exposed Ucp1 knockout mice reveals a distinct brown adipocyte subpopulation (U2). U2 adipocytes exhibit a secretory profile enriched in batokines like growth differentiation factor 15 (GDF15), suggesting a shift toward an endocrine role. Functional analyses reveal that GDF15-GFRAL signaling is required to sustain energy expenditure in adipose tissue (AT). The Ucp1/Gfral knockout increased food intake to compensate for decreased energy expenditure in AT. Additionally, a conserved UCP1-GDF15 regulatory axis in human AT is observed. These findings identify a regulatory brown adipocyte subpopulation emerging in response to UCP1 deficiency, representing a compensatory mechanism for maintaining energy homeostasis in mammals.

Keywords:  CP: metabolism; GDF15; GFRAL; Ucp1 knockout mice; adipose tissue; cold exposure; energy expenditure; single-nucleus RNA sequencing

DOI:  https://doi.org/10.1016/j.celrep.2026.117603
Diabetes. 2026 Jul 08. pii: db250914. [Epub ahead of print]

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

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

ARTICLE HIGHLIGHTS: NAD+ is an essential cofactor for many metabolic reactions. Nicotinamide phosphoribosyltransferase (NAMPT) is an important enzyme in NAD+ biosynthesis, and diminished adipocyte NAD+ and NAMPT have been implicated in metabolic dysfunction. Mice with adipocyte NAMPT overexpression (ANOV) were protected from diet-induced metabolic dysfunction, including adipose tissue inflammation, glucose intolerance, and hepatic steatosis. Extracellular vesicles from ANOV mice improved glucose tolerance in obese mice. Compared with wild-type mice, adipose tissue extracellular vesicles from ANOV mice exhibited marked changes in lipid and metabolite cargoes.

DOI: https://doi.org/10.2337/db25-0914
Mol Metab. 2026 Jul 09. pii: S2212-8778(26)00102-X. [Epub ahead of print] 102418

Endurance Exercise Elicits a Hepatic Memory Associated with Improved Metabolic Function and Protein Secretion.

Yi-Heng Huang, Clay J Weidenhamer, Nasrin Dabirian, Mikaela Kasperek, Donald Molina, Samuel Deyhle, Subhashis Natua, Jaume Amengual, Jacob Matthew Allen, Auinash Kalsotra, Diego Hernández-Saavedra.

  Endurance exercise protects against metabolic dysfunction-associated steatotic liver disease (MASLD), yet whether these effects persist following cessation of training remains unclear. Here, we employed endurance training cycles in mice to isolate the hepatic memory of exercise. Our results indicate that endurance retraining potentiates systemic and hepatic glucoregulatory benefits. Exercise retraining persistently reduced hepatic steatosis, hallmarked by decreases in diacylglycerols and increased phosphatidylcholines (PC). Liver transcriptomic analysis identified lipid and protein secretory pathways induced by endurance retraining. Importantly, retraining enhanced hepatic expression of carboxylesterases, including Ces2b, Ces3a, Ces3b, and Ces4a, and increased circulating carboxylesterase activity and CES4A protein levels. Exercise retraining reduced serum LDL-c and increased HDL-c, while enhancing the delivery of lysoPC and PC, predicted targets of carboxylesterases, to the working muscle. Similarly, mice fed an obesogenic diet demonstrate that this hepatic memory of exercise persists under an obesogenic challenge. In humans, we show that a 6-week training period increases serum CES activity primarily in individuals with prior training. Lastly, our studies identify the PPAR-RXR-clock axis as a potential trigger that may engage the synchronized lipid delivery to skeletal muscle and support fatty acid oxidation. Together, these findings suggest that endurance retraining elicits a hepatic exercise memory characterized by persistent transcriptional reprogramming and lipid remodeling that restore metabolic benefits after inactivity and confer resilience against MASLD.

Keywords:  Liver memory; MASLD; PPARα; carboxylesterases; glucose metabolism; phosphatidylcholines

DOI:  https://doi.org/10.1016/j.molmet.2026.102418
J Cachexia Sarcopenia Muscle. 2026 Aug;17(4): e70335

Divergent AKT Signalling Mechanisms Regulate GLUT4 Translocation and Glucose Uptake in Skeletal Muscle and Adipose Tissue.

Natasha Jaiswal, Matthew Gavin, Louise Lantier, Olivia Yu Yu Ong, David H Wasserman, Paul M Titchenell.

   BACKGROUND: The serine/threonine kinase AKT is a key regulator of glucose and energy metabolism. Prevailing dogma suggests that AKT is an obligate intermediate for glucose uptake in all metabolic tissues and that impaired AKT signalling is a major molecular driver of insulin resistance in obesity. However, whether AKT is universally required for insulin-stimulated glucose uptake across tissues in vivo has remained unresolved.
METHOD: Several mouse models of adipose-specific AKT2 deletion (F-AKT2KO) and skeletal muscle-specific AKT1, AKT2 and combined AKT1/AKT2 knockout mice (M-AKT1KO, M-AKT2KO and M-AKTDKO) were generated. Skeletal muscle and adipose tissues were analysed following in vivo administration of insulin (2 U/kg), using Western blotting, phosphoproteomics, PI(3,4,5)P3 ELISA and mitochondrial respiration assays. Glucose metabolism was assessed using [3H]-2-deoxyglucose uptake, hyperinsulinemic-euglycemic clamps, glucose and insulin tolerance tests. Global phosphoproteomics was performed in insulin-stimulated skeletal muscle lacking AKT isoforms.
RESULTS: Loss of AKT2 in adipose tissue impaired insulin signalling, including reduced pAS160Thr649, and markedly decreased insulin-stimulated glucose uptake (~2-3 fold reduction in F-AKT2KO vs F-Control, p < 0.001, n = 7-11), resulting in systemic insulin resistance. In contrast, M-AKTDKO mice exhibited a robust increase in insulin-stimulated glucose uptake (~3-4 fold increase) despite complete loss of AKT signalling, including pAS160Thr649. Phosphoproteomic analysis of M-AKTDKO (n = 3-4) identified ~7088 phosphosites, with 795 uniquely upregulated in insulin-stimulated M-AKTDKO muscle (fold change > 2, p < 0.05), enriched in PI3K and AMPK pathways. Consistently, ~8-fold (p < 0.05) increase in PIP3 levels was observed in M-AKTDKO muscle in response to insulin. Additionally, AKT deficiency was associated with reduced complex I-dependent mitochondrial respiration (~37% decrease in state 3 respiration), consistent with altered energetic status and AMPK activation. Genetic epistasis experiments demonstrated that both AKT and AMPK activity are required for insulin-stimulated glucose uptake, systemic glucose homeostasis and whole body insulin sensitivity.
CONCLUSION: These findings challenge the long-standing assumption that AKT is universally required for insulin-stimulated glucose uptake in vivo. The study demonstrates that while AKT is essential in adipose tissue, it is dispensable for insulin-stimulated glucose uptake in skeletal muscle. AKT exerts negative feedback on PI3K signalling in both tissues; however, only skeletal muscle engages AMPK in the abscence of AKT to preserve glucose uptake. These findings redefine tissue-specific insulin signalling mechanisms and identify AMPK as a critical downstream target of PI3K that coordinates with AKT to regulate glucose uptake.

Keywords:  AKT signalling; AMPK signalling; GLUT4 translocation; PI3K‐PIP3 pathway; insulin signalling

DOI:  https://doi.org/10.1002/jcsm.70335
J Physiol. 2026 Jul 05.

Fasting-induced glucose intolerance is not impacted by the addition of daily exercise: A randomized crossover study.

Tori Bouck, Alexis Marcotte-Chénard, Darren Barg, Charlie Kanuka, Roderick E Sandilands, Spencer Ursel, Garett Jackson, Arwyn MacIntosh, Sean McIntyre, Sriyashika Nekkanti, Kimberly Day, Hashim Islam, Jonathan P Little.

  Short-term fasting (48-72 h) impairs insulin sensitivity and glucose tolerance, but it is unclear if aerobic exercise - which is known to have insulin-sensitizing effects - can attenuate fasting-induced decrements in glucose homeostasis. To determine whether the addition of exercise to a short-term fast impacts glycaemic responses to refeeding, we implemented a randomized crossover design where 16 healthy adults (8 males and 8 females, 24±4 years) fasted for 48 h with and without the addition of daily cycling (50-min moderate-intensity continuous training + 5×1-min high-intensity interval training) performed at baseline and 24 h into the fast. Glycaemic responses to a mixed meal tolerance test (MMTT) were assessed via capillary measurements and continuous glucose monitoring (CGM) before and after the fast, as well as 24 h after refeeding. Capillary glucose and CGM incremental area under the curve (iAUC) during the 2-h mixed meal tolerance test increased at 48 h fasted relative to baseline (P<0.001), which was unaffected by the addition of exercise (condition × time interaction, P>0.364). The 2-h CGM iAUC reduced 24 h after refeeding compared to 48 h fasted (with or without exercise, P<0.001) but remained elevated relative to baseline (P = 0.01). Exploratory analyses revealed that 2-h capillary (P = 0.020) and CGM (P<0.001) glucose iAUC and plasma glucose (P<0.001) were elevated to a greater extent after refeeding in females compared to males, and females exhibited greater impairments in CGM metrics in the 24 h after refeeding (P<0.01). Our results suggest that combined moderate-intensity continuous training and high-intensity interval training exercise does not attenuate fasting-induced perturbations in glucose homeostasis and that glucose intolerance persists 24 h after refeeding. KEY POINTS: Short-term fasting reduces insulin sensitivity and glucose tolerance, which manifests as exaggerated glycaemic responses to refeeding. Performing exercise during a fast could mitigate fasting-induced glucose intolerance, due to the well-established insulin-sensitizing effects of acute exercise. Here we report that a 48-h fast performed with or without the addition of daily aerobic exercise similarly impaired glucose tolerance upon refeeding and resulted in comparable decrements in continuous glucose monitoring-derived metrics of glycaemic regulation over the 24 h after refeeding. Exercise appears ineffective in reversing fasting-induced glucose intolerance, which could reflect the mechanistic distinction between fasting-induced and pathological forms of insulin resistance.

Keywords:  CGM; continuous glucose monitor; fast; high‐intensity interval training (HIIT); insulin resistance

DOI:  https://doi.org/10.1113/JP291000
Am J Physiol Cell Physiol. 2026 Jul 06.

Skeletal muscle biomass as an underappreciated fate of glucose.

Henning Wackerhage, Moritz Eggelbusch, Juha J Hulmi, Sakari Mäntyselkä.

  Glucose is traditionally viewed as a substrate for ATP production and glycogen storage in skeletal muscle. Here, we review evidence that glucose also serves as a building block for biomass synthesis in proliferating muscle satellite (stem) cells and hypertrophying skeletal muscle fibers, drawing parallels to anabolic metabolic reprogramming in cancer cells. In cancer and other growing cells, increased glucose uptake, aerobic glycolysis (Warburg effect), and the TCA cycle provide substrates for anabolic pathways that generate macromolecules required for growth and proliferation. Radiotracer studies in mammalian cancer and muscle cells demonstrate that approximately 8-15% of the cell dry mass originates from glucose. Mechanistic insights, obtained predominantly from cell culture models, indicate that glucose-derived glycolytic and TCA cycle intermediates provide substrates for serine synthesis and the pentose phosphate pathway, glycine and one-carbon metabolism, non-essential amino acid synthesis, nucleotide and lipid synthesis as well as for epigenetic methylation and acetylation. We further review evidence that human resistance training, hypertrophy through muscle-specific expression of Akt1 in mice, loss or inhibition of myostatin/activin signaling, and other hypertrophy-inducing interventions improve glucose homeostasis under conditions of obesity, insulin resistance, and type 2 diabetes. We discuss the possibility that glucose incorporation into biomass contributes to this effect.

Keywords:  Glucose; Warburg effect; cancer; diabetes mellitus; serine biosynthesis; skeletal muscle; skeletal muscle hypertrophy

DOI:  https://doi.org/10.1152/ajpcell.00295.2026
Am J Physiol Endocrinol Metab. 2026 Jul 07.

Bridging the gap: Multi-omic Insights into Exercise Responses in Post-Menopausal Women.

Rushali Kullachanda Aiyanna, Sisi Wang, Robin Grolaux, Elizabeth Reisman, Bernadette Jones-Freeman, Nir Eynon.

  Post-menopausal women represent the fastest-growing demographic at risk of sarcopenia and cardiometabolic disease, yet exercise biology research remains disproportionately derived from male or hormone-replete phenotypes. Menopause constitutes a chronic endocrine perturbation characterized by sustained reductions in estrogen and progesterone and altered androgen balance, superimposed on the acute and chronic perturbations induced by exercise. This hormonal shift modifies substrate metabolism, inflammation, redox balance, and recovery capacity, factors that shape molecular responses to exercise across tissues and time. Here, we synthesize current evidence on exercise responses in post-menopausal females across genomics, epigenomics, transcriptomics, proteomics and metabolomics/lipidomics. Across omics layers, direct data in post-menopausal cohorts remain limited, with frequent under-reporting of menopausal status, hormone therapy exposure, circulating hormone concentrations, medication use, and bio sampling timing relative to exercise and hormone dosing. We outline a menopause-aware framework for exercise-omics that prioritizes endocrine stratification, repeated sampling across exercise and recovery, and integrative multi-omics approaches linking molecular responses to functional outcomes. We also outline minimum reporting standards to improve reproducibility, inclusivity, and translational relevance. Advancing menopause-aware exercise-omics will be essential for developing precision exercise strategies that improve healthspan and functional independence in later life.

Keywords:  Exercise; epigenomics; lipidomics; menopause; metabolomics; proteomics

DOI:  https://doi.org/10.1152/ajpendo.00172.2026