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

TitleA branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance.
Publication TypeJournal Article
Year of Publication2016
AuthorsJang, C, Oh, SF, Wada, S, Rowe, GC, Liu, L, Chan, MChun, Rhee, J, Hoshino, A, Kim, B, Ibrahim, A, Baca, LG, Kim, E, Ghosh, CC, Parikh, SM, Jiang, A, Chu, Q, Forman, DE, Lecker, SH, Krishnaiah, S, Rabinowitz, JD, Weljie, AM, Baur, JA, Kasper, DL, Arany, Z
JournalNat Med
Volume22
Issue4
Pagination421-6
Date Published2016 Apr
ISSN1546-170X
KeywordsAmino Acids, Branched-Chain, Animals, Fatty Acids, Humans, Hydroxybutyrates, Insulin, Insulin Resistance, Mice, Mice, Inbred NOD, Muscle, Skeletal, Obesity, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Transcription Factors
Abstract

<p>Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, 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. </p>

DOI10.1038/nm.4057
Alternate JournalNat. Med.
PubMed ID26950361
PubMed Central IDPMC4949205
Grant ListR01 DK098656 / DK / NIDDK NIH HHS / United States
R01 DK095072 / DK / NIDDK NIH HHS / United States
AR062128 / AR / NIAMS NIH HHS / United States
HL094499 / HL / NHLBI NIH HHS / United States
K01 AR062128 / AR / NIAMS NIH HHS / United States
DK098656 / DK / NIDDK NIH HHS / United States
K01 DK102771 / DK / NIDDK NIH HHS / United States
DK095072 / DK / NIDDK NIH HHS / United States
R01 HL094499 / HL / NHLBI NIH HHS / United States
R01 HL093234 / HL / NHLBI NIH HHS / United States
HL093234 / HL / NHLBI NIH HHS / United States
5 T32 GM7592-35 / GM / NIGMS NIH HHS / United States
R01 HL125275 / HL / NHLBI NIH HHS / United States
HL125275 / HL / NHLBI NIH HHS / United States
T32 GM007592 / GM / NIGMS NIH HHS / United States
P30 DK057521 / DK / NIDDK NIH HHS / United States
P01 DK049210 / DK / NIDDK NIH HHS / United States
T32 HL007374 / HL / NHLBI NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
DK049210 / DK / NIDDK NIH HHS / United States
R01 AG043483 / AG / NIA NIH HHS / United States