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A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance

Nature Medicine volume 22, pages 421–426 (2016)Cite this article

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Abstract

Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear1,2,3. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species4, a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.

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Figure 1: PGC-1α expression in muscle cells induces the secretion of a paracrine activity that stimulates endothelial fatty acid (FA) transport.
Figure 2: Identification of 3-HIB as the paracrine factor.
Figure 3: 3-HIB is generated from valine catabolism that is induced by PGC-1α, and it stimulates endothelial fatty acid uptake.
Figure 4: 3-HIB induces fatty acid uptake in vivo and causes glucose intolerance.

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Acknowledgements

Human endothelial colony forming cells (ECFCs) were kindly provided by J. Bischoff (Boston Children's Hospital). Fatp4−/− and Cd36−/− mice were kindly provided by J. Miner (Washington University School of Medicine) and J. Lawler (Harvard Medical School), respectively. Flt1flox/flox and Kdrflox/flox mice were kindly provided by Genentech. C.J. is supported by the Lotte Scholarship and American Heart Association (AHA). S.F.O. is supported by the Crohn's and Colitis Foundation of America (Research Fellowship Award). S.W. is supported by the Toyobo Biotechnology Foundation. G.C.R. is supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR062128). J.R. is supported by the US National Institutes of Health (5 T32 GM7592-35). S.M.P. is supported by the US National Heart, Lung, and Blood Institute (NHLBI) (HL093234; HL125275) and the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK095072). Q.C. and J.A.B. are supported by the NIDDK (DK098656; DK049210). Z.A. is supported by the NHLBI (HL094499), the AHA and the Geis Realty Group Emerging Initiatives Fund and Dean and Ann Geis.

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Author notes

  1. Glenn C Rowe

    Present address: Present address: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.,

  2. Cholsoon Jang and Sungwhan F Oh: These authors contributed equally to this work.

Authors and Affiliations

  1. Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Cholsoon Jang, Shogo Wada, Atsushi Hoshino, Boa Kim, Ayon Ibrahim, Qingwei Chu, Saikumari Krishnaiah, Aalim M Weljie, Joseph A Baur & Zoltan Arany

  2. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Cholsoon Jang, Glenn C Rowe, Laura Liu, Mun Chun Chan, James Rhee, Luisa G Baca, Esl Kim, Chandra C Ghosh, Samir M Parikh, Aihua Jiang & Stewart H Lecker

  3. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA

    Sungwhan F Oh & Dennis L Kasper

  4. Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA

    James Rhee

  5. Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Daniel E Forman

  6. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA

    Joshua D Rabinowitz

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Contributions

C.J. led the studies and was directly involved in most experiments. S.F.O. assigned the structure of the paracrine factor as 3-HIB and performed mass spectrometric profiling. S.W., G.C.R., L.L., M.C.C., J.R., A.H., B.K., A.I., L.G.B., E.K. and A.J. assisted with experiments throughout, including qPCR, cell culture and animal studies. Q.C. and J.A.B. performed the mouse clamp studies. S.K. and A.M.W. performed the lipidomic studies. D.E.F. and S.H.L. isolated the human muscle biopsies. C.C.G. and S.M.P. performed the TEER studies. J.D.R. performed the metabolic flux analysis. D.L.K. and Z.A. oversaw the studies. C.J. and Z.A. designed experiments, interpreted results and wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Zoltan Arany.

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The authors declare no competing financial interests.

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Supplementary Figures 1–10 and Supplementary Table 1 (PDF 2717 kb)

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Jang, C., Oh, S., Wada, S. et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med 22, 421–426 (2016). https://doi.org/10.1038/nm.4057

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