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.