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TGF-?2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism.

ABSTRACT: Exercise improves health and well-being across diverse organ systems, and elucidating mechanisms underlying the beneficial effects of exercise can lead to new therapies. Here, we show that transforming growth factor-?2 (TGF-?2) is secreted from adipose tissue in response to exercise and improves glucose tolerance in mice. We identify TGF-?2 as an exercise-induced adipokine in a gene expression analysis of human subcutaneous adipose tissue biopsies after exercise training. In mice, exercise training increases TGF-?2 in scWAT, serum, and its secretion from fat explants. Transplanting scWAT from exercise-trained wild type mice, but not from adipose tissue-specific Tgfb2-/- mice, into sedentary mice improves glucose tolerance. TGF-?2 treatment reverses the detrimental metabolic effects of high fat feeding in mice. Lactate, a metabolite released from muscle during exercise, stimulates TGF-?2 expression in human adipocytes. Administration of the lactate-lowering agent dichloroacetate during exercise training in mice decreases circulating TGF-?2 levels and reduces exercise-stimulated improvements in glucose tolerance. Thus, exercise training improves systemic metabolism through inter-organ communication with fat via a lactate-TGF-?2-signaling cycle.

SUBMITTER: Takahashi H

PROVIDER: S-EPMC6481955 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism.

Takahashi Hirokazu H Alves Christiano R R CRR Stanford Kristin I KI Middelbeek Roeland J W RJW Nigro Pasquale P Ryan Rebecca E RE Xue Ruidan R Sakaguchi Masaji M Lynes Matthew D MD So Kawai K Mul Joram D JD Lee Min-Young MY Balan Estelle E Pan Hui H Dreyfuss Jonathan M JM Hirshman Michael F MF Azhar Mohamad M Hannukainen Jarna C JC Nuutila Pirjo P Kalliokoski Kari K KK Nielsen Søren S Pedersen Bente K BK Kahn C Ronald CR Tseng Yu-Hua YH Goodyear Laurie J LJ

Nature metabolism 20190211 2

Exercise improves health and well-being across diverse organ systems, and elucidating mechanisms underlying the beneficial effects of exercise can lead to new therapies. Here, we show that transforming growth factor-β2 (TGF-β2) is secreted from adipose tissue in response to exercise and improves glucose tolerance in mice. We identify TGF-β2 as an exercise-induced adipokine in a gene expression analysis of human subcutaneous adipose tissue biopsies after exercise training. In mice, exercise train ...[more]

PMID: 31032475

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Project description:BACKGROUND:Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity-induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth. METHODS:We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart. RESULTS:Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (GlycoLo mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of GlycoLo mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (GlycoHi mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose-fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling. CONCLUSIONS:Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.

Dataset Information

TGF-?2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism.

Publications

TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism.

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