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


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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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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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).

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