MTOR complex 2 (mTORC2) regulation of hepatic gene expression

Abstract

mTORC2 has been connected to various disorders, including diabetes and cancer. It is required for insulin‐mediated suppression of hepatic glucose production. Our aim was to examine the role of mTORC2 in the regulation of liver metabolism. Control mice and RKO mice (liver‐specific knockout of Rictor, an mTORC2 constituent) were fasted overnight, fed for 3 hr, then sacrificed. Liver RNA (n = 4 per group) was analyzed using Affymetrix Genechip Mouse Gene 1.0 ST arrays. Gene Set Enrichment Analysis (GSEA) revealed upregulation of three categories of genes in the RKO mice: ribosomal proteins, TCA cycle/oxidative phosphorylation, and components of the 26S proteosome. GSEA results were consistent using both KEGG and Reactome datasets. Ingenuity Pathway Analysis (IPA) showed gene function categories relating to carbohydrate and lipid metabolism. In addition, three transcription factors were significantly altered in the RKO mice. FoxO1 was activated relative to the controls while CTNNB1 and NR1L3 were inactivated. Our results indicate that mTORC2 has broad effects on hepatic gene expression. mTORC2 is linked, in particular, to carbohydrate, lipid and mitochondrial energy metabolism. It also appears to regulate genes involved in ribosome and proteosome biogenesis. Supported by grants from NIH/NIA (DWL), the American Federation of Aging Research (DMS), Howard Hughes Medical Institute (DMS), and NIH/NICHD (PAG).