Thioesterase Superfamily Member 2 (Them2) Channels Fatty Acids to Glycerol‐3‐Phosphate Acyltransferase‐1 (GPAT1): Role in Hepatic Insulin Resistance

Them2 is a mitochondria‐associated acyl‐CoA thioesterase, which promotes fatty acid oxidation within hepatocytes apparently by generating free fatty acids that are re‐esterified to CoA by long chain acyl‐CoA synthetase 1 (ACSL1) for uptake by carnitine palmitoyl transferase 1. ACSL1‐generated fatty acyl‐CoAs may also become substrates for GPAT1, which initiates the synthesis of glycerolipids. Diacylglycerols and phosphatidic acid suppress insulin signaling by activating PKCε or inactivating mTORC2, respectively, and GPAT1 overexpression in liver promotes hepatic insulin resistance. Because livers of Them2 ‐/‐ mice exhibit increased sensitivity to insulin, we examined whether Them2 promotes GPAT1‐mediated suppression of insulin signaling. Using recombinant adenovirus, GPAT1 or GFP was overexpressed in mouse livers. GPAT1 but not GFP overexpression promoted hepatic synthesis of glycerolipids in both Them2 +/+ and Them2 ‐/‐ mice. As evidenced by increased ratios of membrane/cytosolic PKCε, GPAT1 overexpression activated PKCε in livers of Them2 +/+ mice, an effect that was attenuated in the absence of Them2 expression. Consistent with the contribution of Them2 to GPAT1‐induced hepatic insulin resistance, when primary mouse hepatocytes were infected with GPAT1 adenovirus, insulin‐mediated Akt phosphorylation was increased at S473 and T308 in the absence of Them2 expression. These findings implicate Them2 in channeling fatty acids to GPAT1 and in the pathogenesis of hepatic insulin resistance. Support: NIH DK48873, DK56626 and DK56598; Sumitomo Life Welfare and Culture Foundation