Local Suppression of Dgat2 Augments Fatty Acid Oxidation in Skeletal Muscle in High-Fat Diet-Fed Mice

Diacylglycerol acyltransferase 2 (DGAT2) codes an enzyme which synthesize triglyceride by esterifying fatty acid to last portion of diacylglycerol backbone, and contributes to intramyocellular lipid metabolism. Small interfering RNA (siRNA)-mediated knockdown of Dgat2 was previously shown to reduce AKT phosphorylation and glucose uptake, decrease fatty acid partitioning into triglycerides, and increase free fatty acid release and oxidation in skeletal muscle cells. The current study aimed to determine whether Dgat2 knockdown affects lipid and glucose metabolism in glycolytic muscle (GM) and oxidative muscle (OM) under high-fat diet conditions, consistent with our previous in vitro findings. Male C57BL/6J mice were fed high-fat diet, and treated with Dgat2 or control-siRNA, and the effects were compared in different muscle types. Muscle Dgat2 suppression reduced intramuscular triglyceride content by up to 38.2% whereas increased circulating triglyceride levels. In addition, decreased Gpat3 mRNA levels supported a reduction in lipid esterification capacity. Dgat2 suppression increased the integration of C14-tagged fatty acids into acid-soluble metabolites, and altered gene expressions related to glucose utilization; GLUT4 protein were decreased and Pdk2 mRNA increased in both GM and OM fibers. GM exhibited decreased AKT phosphorylation about 50%, whereas OM showed no change in AKT phosphorylation. Noticeably OM exhibited reduced Hk2 and glycogen accumulation. Together, these findings suggest that muscle Dgat2 inhibition redirects fatty acid channeling from triglyceride storage toward oxidation in vivo, with accompanying changes in glucose metabolism-related markers. These results extend our previous cell-based findings to a more physiologically relevant setting, while highlighting distinct response patterns in GM and OM.