¹ Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 300 Chunchun-dong, Jangan-gu, Suwon, Gyeonggi-do 440-746, Korea
² Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
³ Lee Gil Ya Cancer and Diabetes Institute, Gil Medical Center, Gachon University of Medicine and Science, Incheon 405-760, Korea
⁴ Division of Endocrinology, Gil Medical Center, Gachon University of Medicine and Science, Incheon 405-760, Korea
⁵ Institute of Biomedical Science and Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul133-791, Korea

^*Corresponding author

⁶ These authors contributed equally to this work

TORC2 is a major transcriptional coactivator for hepatic glucose production. Insulin impedes gluconeogenesis by inhibiting TORC2 via SIK2-dependent phosphorylation at Ser171. Interruption of this process greatly perturbs hepatic glucose metabolism, thus promoting hyperglycemia in rodents. Here, we show that hyperactivation of TORC2 would exacerbate insulin resistance by enhancing expression of LIPIN1, a mammalian phosphatidic acid phosphatase for diacylglycerol (DAG) synthesis. Diet-induced or genetic obesity increases LIPIN1 expression in mouse liver, and TORC2 is responsible for its transcriptional activation. While overexpression of LIPIN1 disturbs hepatic insulin signaling, knockdown of LIPIN1 ameliorates hyperglycemia and insulin resistance by reducing DAG and PKCɛ activity in db/db mice. Finally, TORC2-mediated insulin resistance is partially rescued by concomitant knockdown of LIPIN1, confirming the critical role of LIPIN1 in the perturbation of hepatic insulin signaling. These data propose that dysregulation of TORC2 would further exaggerate insulin resistance and promote type 2 diabetes in a LIPIN1-dependent manner.