A metabolite of branched chain amino acids drives vascular fatty acid transport and causes glucose intolerance

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. Insulin resistance in skeletal muscle stems from excess accumulation of lipid species, 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 identify 3-hydroxy-isobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a novel paracrine regulator of trans-endothelial transport of fatty acids. PGC-1α, a transcriptional co-activator that regulates broad programs of fatty acid consumption, induces the secretion from muscle of 3-HIB, which then triggers fatty acid uptake and transport in endothelial cells. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the promotion of endothelial fatty acid uptake. Providing animals with 3-HIB in drinking water, or inducing 3-HIB levels in skeletal muscle by over-expressing PGC-1α, stimulates muscle to take up fatty acids in vivo, leading to muscle lipid accumulation, and systemic glucose intolerance. 3-HIB levels are elevated in muscle from patients with diabetes. These data thus unveil a novel mechanism that regulates trans-endothelial flux of fatty acids, revealing 3-HIB as a new bioactive signaling metabolite that links the regulation of fatty acid flux to BCAA catabolism and provides a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.