Abstract

Thioesterase superfamily member 2 (Them2) is highly expressed in 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, insulin resistance and hepatic steatosis, liver-specific Them2-/- mice remain susceptible. To explore the contribution of Them2 in extrahepatic tissues, we created mice with Them2 deleted in skeletal muscle (S-Them2-/-), cardiac muscle (C-Them2-/-) or adipose tissue (A-Them2-/-). When fed a high-fat diet, S-Them2-/- but not C-Them2-/- or A-Them2-/- mice exhibited reduced weight gain. Only S-Them2-/- mice exhibited improved glucose homeostasis together with improved insulin sensitivity in skeletal muscle. Increased rates of fatty acid oxidation in skeletal muscle of S-Them2-/- mice were reflected in alterations in skeletal muscle metabolites, including short chain fatty acids, branched chain amino acids and the pentose phosphate pathway. Protection from diet-induced hepatic steatosis in S-Them2-/- mice was attributable to increased VLDL triglyceride secretion rates in support of demands of increased muscle fatty acid utilization. These results reveal a key role for skeletal muscle Them2 in the pathogenesis of diet-induced obesity, insulin resistance and hepatic steatosis.