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.
Highlights d A chemical screen identifies novel inhibitors of endothelial fatty acid uptake d Endothelial fatty acid uptake and transport requires specifically mitochondrial ATP d Endothelial mitochondria are proximally positioned to the ER d ER-borne FATP4 uses mitochondrial ATP to mediate vectorial acylation of fatty acids
Intracellular metabolism in skeletal muscle has been studied for more than a century and is the stuff of textbooks. In contrast, the extracellular secretion of metabolites by muscle cells, and their effects on non-muscle cells near or far, has been investigated much less extensively. Here, we describe a number of cases in which striated muscle secretes a metabolite that elicits complex responses in other cells or tissues, with involvements in normal physiology as well as obesity, type II diabetes, and cardiac remodeling. We focus on two recently identified secreted catabolic products of branched chain amino acid breakdown, β-aminoisobutyric acid and 3-hydroxyisobutyrate, and discuss common themes of inter-cellular signaling pathways driven by secreted metabolites.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.