A branched chain amino acid metabolite drives vascular transport of fat and causes insulin resistance
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Author
Jang, Cholsoon
Wada, Shogo
Rowe, Glenn C
Chan, Mun Chun
Hoshino, Atsushi
Kim, Boa
Ibrahim, Ayon
Baca, Luisa G
Kim, Esl
Jiang, Aihua
Chu, Qingwei
Forman, Daniel E.
Krishnaiah, Saikumari
Rabinowitz, Joshua D
Weljie, Aalim M
Baur, Joseph A
Arany, Zoltan
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nm.4057Metadata
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Jang, C., S. F. Oh, S. Wada, G. C. Rowe, L. Liu, M. C. Chan, J. Rhee, et al. 2016. “A branched chain amino acid metabolite drives vascular transport of fat and causes insulin resistance.” Nature medicine 22 (4): 421-426. doi:10.1038/nm.4057. http://dx.doi.org/10.1038/nm.4057.Abstract
Epidemiological and experimental data implicate branched chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms underlying this link remain unclear.1–3 Insulin resistance in skeletal muscle stems from excess accumulation of lipid species4, a process that requires blood-borne lipids to first traverse the blood vessel wall. Little is known, however, of how this trans-endothelial transport occurs or is regulated. Here, we leverage PGC-1α, a transcriptional coactivator that regulates broad programs of FA consumption, to identify 3-hydroxy-isobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a novel paracrine regulator of trans-endothelial fatty acids (FA) transport. 3-HIB is secreted from muscle cells, activates endothelial FA transport, stimulates muscle FA uptake in vivo, and promotes muscle lipid accumulation and insulin resistance in animals. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the promotion of endothelial FA uptake. 3-HIB levels are elevated in muscle from db/db mice and from subjects with diabetes. These data thus unveil a novel mechanism that regulates trans-endothelial flux of FAs, revealing 3-HIB as a new bioactive signaling metabolite that links the regulation of FA flux to BCAA catabolism and provides a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949205/pdf/Terms of Use
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