Up-regulation of thioesterase superfamily member 2 in skeletal muscle promotes hepatic steatosis and insulin resistance in mice

Background and 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 (HS), and insulin resistance (IR), 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 HS and IR. Approach and Results Upon observing IR and up-regulation of Them2 in skeletal, but not cardiac, muscle of high-fat-diet (HFD)-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 an HFD, 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 HFD-induced HS by increasing VLDL triglyceride secretion rates in response to greater demand. Increases in insulin sensitivity were further attributable to alterations in production of skeletal muscle metabolites, including short-chain fatty acids, branched-chain amino acids, and pentose phosphate pathway intermediates, as well as in expression of myokines that modulate insulin responsiveness. Conclusions These results reveal a key role for skeletal muscle Them2 in the pathogenesis of HS and IR and implicate it as a target in the management of NAFLD.