Thioesterase superfamily member 2 (Them2; synonym Acot13) is enriched in oxidative tissues, associated with mitochondria, and relatively specific for long chain fatty acyl-CoA substrates. Using Them2-/- mice, we have demonstrated key roles for Them2 in regulating hepatic glucose and lipid metabolism. Them2 activity in vitro is increased when it interacts with phosphatidylcholine transfer protein (PC-TP), a cytosolic lipid binding protein. Them2-/- and Pctp-/- mice exhibit enhanced hepatic insulin sensitivity and increased adaptive thermogenesis, and Them2-/- mice are also resistant to diet-induced hepatic steatosis. We have demonstrated that a Them2-PC-TP complex suppresses insulin signaling, but additionally that Them2 alone has a primary role in promoting mitochondrial oxidation of fatty acids and glucose in the liver.