LAUSR

BACKGROUND & AIMS Thioesterase superfamily member 2 (Them2) is highly expressed in liver and oxidative tissues, where it hydrolyzes long chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 (Them2-/- ) are protected against diet-induced obesity, hepatic steatosis and insulin resistance, liver-specific Them2-/- mice remain susceptible. The aim of this study was to test whether Them2 activity in extrahepatic oxidative tissues is a primary determinant of hepatic steatosis and insulin resistance. APPROACH & RESULTS Upon observing insulin resistance and upregulation of Them2 in skeletal, but not cardiac muscle of high-fat fed wild type compared to Them2-/- mice, we created mice with Them2 specifically deleted in skeletal (S-Them2-/- ) and cardiac muscle (C-Them2-/- ), as well as in adipose tissue (A-Them2-/- ). When fed a high-fat diet, S-Them2-/- but not C-Them2-/- or A-Them2-/- mice exhibited reduced weight gain and improved glucose homeostasis and insulin sensitivity. Reconstitution of Them2 expression in skeletal muscle of global Them2-/- mice using adeno-associated virus was sufficient to restore excess weight gain. Increased rates of fatty acid oxidation in skeletal muscle of S-Them2-/- mice contributed to protection from high-fat diet-induced hepatic steatosis by increasing VLDL triglyceride secretion rates in response to greater demand. Increases in insulin sensitivity were further attributable to alterations in the production of skeletal muscle metabolites, including short chain fatty acids, branched chain amino acids and pentose phosphate pathway intermediates, as well as in the expression of myokines that modulate insulin responsiveness. CONCLUSIONS These results reveal a key role for skeletal muscle Them2 in the pathogenesis of hepatic steatosis and insulin resistance, and implicate it as a target in the management of non-alcoholic fatty liver disease.