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

Hirokazu Takahashi, Christiano R.R. Alves, Kristin I. Stanford, Roeland J.W. Middelbeek, Pasquale Nigro, Rebecca E. Ryan, Ruidan Xue, Masaji Sakaguchi, Matthew D. Lynes, Kawai So, Joram D. Mul, Min Young Lee, Estelle Balan, Hui Pan, Jonathan M. Dreyfuss, Michael F. Hirshman, Mohamad Azhar, Jarna C. Hannukainen, Pirjo Nuutila, Kari K. KalliokoskiSøren Nielsen, Bente K. Pedersen, C. Ronald Kahn, Yu Hua Tseng, Laurie J. Goodyear*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

154 Citations (Scopus)

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-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 training increases TGF-β2 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-β2 treatment reverses the detrimental metabolic effects of high-fat feeding in mice. Lactate, a metabolite released from muscle during exercise, stimulates TGF-β2 expression in human adipocytes. Administration of the lactate-lowering agent dichloroacetate during exercise training in mice decreases circulating TGF-β2 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-β2 signaling cycle.

Original languageEnglish
JournalNature Metabolism
Volume1
Issue number2
Pages (from-to)291-303
ISSN2522-5812
DOIs
Publication statusPublished - 2019

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