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

Nature Metabolism volume 1, pages 291–303 (2019)Cite this article

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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.

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Fig. 1: TGF-β2 is an exercise-induced adipokine.
Fig. 2: Recombinant TGF-β2 treatment stimulates glucose uptake and OCR in vitro.
Fig. 3: TGF-β2 infusion via an osmotic pump stimulates tissue glucose uptake and muscle OCR in mice.
Fig. 4: TGF-β2 infusion via an osmotic pump ameliorates the effects of a HFD in mice.
Fig. 5: TGF-β2 treatment attenuates HFD-induced inflammation in adipose tissue.
Fig. 6: Lactate produced by exercise training stimulates TGF-β2.

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Data availability

All data underlying the findings reported in this manuscript are provided as part of the article. Source data are available online. Mouse and human microarray data are available in the Gene Expression Omnibus database under accession numbers GSE68161 and GSE116801. The raw data that are not already presented in the figures are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by NIH grants R01DK099511 and R01DK112283 (to L.J.G.), K23DK114550 (to R.J.W.M.) and the Joslin Diabetes Center DRC (P30 DK36836). H.T. was supported by individual research fellowships from the Uehara Memorial Foundation and Sumitomo Life Welfare Foundation. Y.-H.T. was supported by NIH grant grants R01DK077097 and R01DK102898. K.I.S. was supported by R01-HL138738. M.D.L. was supported by NIH grants T32DK007260, F32DK102320 and K01DK111714. M.A. was supported by NIH grants R01HL126705 and R01HL145064, and American Heart Association Grant-in-Aid grant 17GRNT33650018. B.K.P. and the Centre for Physical Activity Research were supported by a grant from TrygFonden. We thank K. Longval and A. Clermont from the Joslin Diabetes Center Animal Physiology Core, and L. Kannan from Joslin Special Assay Core. We thank L. Rowland, S. Lessard and A. Queiroz for helpful scientific discussions, and N. Prince and C. Doherty for technical support.

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Author notes

  1. These authors contributed equally: Hirokazu Takahashi, Christiano R. R. Alves.

  2. Deceased: Ruidan Xue.

Authors and Affiliations

  1. Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    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, Michael F. Hirshman, C. Ronald Kahn, Yu-Hua Tseng & Laurie J. Goodyear

  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

    Kristin I. Stanford

  3. Bioinformatics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    Hui Pan & Jonathan M. Dreyfuss

  4. Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, SC, USA

    Mohamad Azhar

  5. Turku PET Centre, University of Turku, Turku, Finland

    Jarna C. Hannukainen, Pirjo Nuutila & Kari K. Kalliokoski

  6. The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Søren Nielsen & Bente K. Pedersen

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  1. Hirokazu Takahashi
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Contributions

H.T. and C.R.R.A. designed research, carried out experiments, analysed data and wrote the paper. K.I.S. performed experiments with trained mice. R.J.W.M. performed and analysed human data. P. Nigro carried out all experiments of adipocyte incubation. R.E.R. carried out experiments and analysed data with Tgfb2-knockout mice and TGF-β2-treated mice. R.X. designed and performed Seahorse assays and provided human white preadipocytes. M.S. carried out experiments and analysed data of cell sorting. M.D.L. carried out in vivo imaging studies for fatty acid uptake. K.S. and J.D.M. performed genotyping of Tgfb2-knockout mice and cell experiments. J.M.D. carried out correlation analysis of microarray data and analysed bioinformatic data. M.-Y.L. carried out gene expression analysis of human adipose tissue. E.B. carried out fatty acid uptake in vitro and Seahorse assays. H.P. and J.M.D. performed bioinformatics analysis. M.F.H. performed in vivo experiments and supervised all experiments. M.A. established and provided Tgfb2-knockout mice. J.C.H., P. Nuutila, K.K.K., B.K.P. and S.N. carried out and provided human samples. C.R.K. supervised in vivo and in vitro experiments with adipocytes or adipose tissue. Y.-H.T. supervised experiments with human preadipocytes and provided immortalized brown preadipocytes. L.J.G. directed the research project, designed experiments and wrote the paper. All authors participated in the manuscript review. All authors approved the final manuscript.

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Correspondence to Laurie J. Goodyear.

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Supplementary Information

Supplementary Figures 1–14 and Supplementary Tables 2 and 3

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Supplementary Table 1

Human scWAT gene expression data (human_gene_stats_unweighted)

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Takahashi, H., Alves, C.R.R., Stanford, K.I. et al. TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat Metab 1, 291–303 (2019). https://doi.org/10.1038/s42255-018-0030-7

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