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

  • Nat Metab. 2019 Feb;1(2):291-303. doi: 10.1038/s42255-018-0030-7.
Hirokazu Takahashi  #  1 ,  Christiano R R Alves  #  1 ,  Kristin I Stanford  1  2 ,  Roeland J W Middelbeek  1 ,  Pasquale Nigro  1 ,  Rebecca E Ryan  1 ,  Ruidan Xue  1 ,  Masaji Sakaguchi  1 ,  Matthew D Lynes  1 ,  Kawai So  1 ,  Joram D Mul  1 ,  Min-Young Lee  1 ,  Estelle Balan  1 ,  Hui Pan  3 ,  Jonathan M Dreyfuss  3 ,  Michael F Hirshman  1 ,  Mohamad Azhar  4 ,  Jarna C Hannukainen  5 ,  Pirjo Nuutila  5 ,  Kari K Kalliokoski  5 ,  Søren Nielsen  6 ,  Bente K Pedersen  6 ,  C Ronald Kahn  1 ,  Yu-Hua Tseng  1 ,  Laurie J Goodyear  7
Affiliations
  • 1. Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
  • 2. Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • 3. Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
  • 4. Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, USA.
  • 5. Turku PET Centre, University of Turku, Turku, Finland.
  • 6. The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
  • 7. Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 31032475 DOI: 10.1038/s42255-018-0030-7
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 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-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.

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