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

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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References

  1. Wang, T.J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).

    Article  Google Scholar 

  2. Newgard, C.B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).

    Article  CAS  Google Scholar 

  3. Newgard, C.B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 15, 606–614 (2012).

    Article  CAS  Google Scholar 

  4. Shulman, G.I. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N. Engl. J. Med. 371, 1131–1141 (2014).

    Article  Google Scholar 

  5. Chan, M.C. & Arany, Z. The many roles of PGC-1α in muscle—recent developments. Metabolism 63, 441–451 (2014).

    Article  CAS  Google Scholar 

  6. Handschin, C. & Spiegelman, B.M. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr. Rev. 27, 728–735 (2006).

    Article  CAS  Google Scholar 

  7. Arany, Z. et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 451, 1008–1012 (2008).

    Article  CAS  Google Scholar 

  8. Hagberg, C.E. et al. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464, 917–921 (2010).

    Article  CAS  Google Scholar 

  9. Roberts, L.D. et al. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96–108 (2014).

    Article  CAS  Google Scholar 

  10. Lin, J. et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418, 797–801 (2002).

    Article  CAS  Google Scholar 

  11. Arany, Z. et al. The transcriptional coactivator PGC-1β drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab. 5, 35–46 (2007).

    Article  CAS  Google Scholar 

  12. Hatazawa, Y. et al. Metabolomic analysis of the skeletal muscle of mice overexpressing PGC-1α. PLoS One 10, e0129084 (2015).

    Article  Google Scholar 

  13. Henkin, A.H. et al. Real-time noninvasive imaging of fatty acid uptake in vivo. ACS Chem. Biol. 7, 1884–1891 (2012).

    Article  CAS  Google Scholar 

  14. Choi, C.S. et al. Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc. Natl. Acad. Sci. USA 105, 19926–19931 (2008).

    Article  CAS  Google Scholar 

  15. Avogaro, A. & Bier, D.M. Contribution of 3-hydroxyisobutyrate to the measurement of 3-hydroxybutyrate in human plasma: comparison of enzymatic and gas-liquid chromatography-mass spectrometry assays in normal and in diabetic subjects. J. Lipid Res. 30, 1811–1817 (1989).

    CAS  PubMed  Google Scholar 

  16. Giesbertz, P. et al. Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes. Diabetologia 58, 2133–2143 (2015).

    Article  CAS  Google Scholar 

  17. Mullen, E. & Ohlendieck, K. Proteomic profiling of non-obese type 2 diabetic skeletal muscle. Int. J. Mol. Med. 25, 445–458 (2010).

    CAS  PubMed  Google Scholar 

  18. Sasaki, M. et al. A severely brain-damaged case of 3-hydroxyisobutyric aciduria. Brain Dev. 23, 243–245 (2001).

    Article  CAS  Google Scholar 

  19. Abbott, N.J., Hughes, C.C., Revest, P.A. & Greenwood, J. Development and characterisation of a rat brain capillary endothelial culture: towards an in vitro blood-brain barrier. J. Cell Sci. 103, 23–37 (1992).

    CAS  PubMed  Google Scholar 

  20. Xie, Z. et al. Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome). Blood 119, 4321–4332 (2012).

    Article  CAS  Google Scholar 

  21. Rowe, G.C. et al. Disconnecting mitochondrial content from respiratory chain capacity in PGC-1-deficient skeletal muscle. Cell Reports 3, 1449–1456 (2013).

    Article  CAS  Google Scholar 

  22. Sawada, N. et al. Endothelial PGC-1α mediates vascular dysfunction in diabetes. Cell Metab. 19, 246–258 (2014).

    Article  CAS  Google Scholar 

  23. Darland, D.C. & D'Amore, P.A. TGFβ is required for the formation of capillary-like structures in three-dimensional cocultures of 10T1/2 and endothelial cells. Angiogenesis 4, 11–20 (2001).

    Article  CAS  Google Scholar 

  24. Titchenell, P.M., Chu, Q., Monks, B.R. & Birnbaum, M.J. Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo. Nat. Commun. 6, 7078 (2015).

    Article  CAS  Google Scholar 

  25. Forman, D.E. et al. Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure. J. Card. Fail. 20, 422–430 (2014).

    Article  CAS  Google Scholar 

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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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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.

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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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