Journal
NATURE METABOLISM
Volume 1, Issue 2, Pages 291-303Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-018-0030-7
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Funding
- NIH [R01DK099511, R01DK112283, K23DK114550, R01DK077097, R01DK102898, T32DK007260, F32DK102320, K01DK111714, R01HL126705, R01HL145064]
- Joslin Diabetes Center DRC [P30 DK36836]
- Uehara Memorial Foundation
- Sumitomo Life Welfare Foundation
- American Heart Association [17GRNT33650018]
- TrygFonden
- [R01-HL138738]
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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-beta 2 (TGF-beta 2) is secreted from adipose tissue in response to exercise and improves glucose tolerance in mice. We identify TGF-beta 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-beta 2 in subcutaneous white adipose tissue (scWAT) and 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-beta 2 treatment reverses the detrimental metabolic effects of high-fat feeding in mice. Lactate, a metabolite released from muscle during exercise, stimulates TGF-beta 2 expression in human adipocytes. Administration of the lactate-lowering agent dichloroacetate during exercise training in mice decreases circulating TGF-beta 2 levels and reduces exercise-stimulated improvements in glucose tolerance. Thus, exercise training improves systemic metabolism through interorgan communication with fat via a lactate-TGF-beta 2 signaling cycle.
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