TORC2 Regulates Hepatic Insulin Signaling via a Mammalian Phosphatidic Acid Phosphatase, LIPIN1

Dongryeol Ryu, Kyoung Jin Oh, Hee Yeon Jo, Susan Hedrick, Yo Na Kim, Yu Jin Hwang, Tae Sik Park, Joong Soo Han, Cheol Soo Choi, Marc Montminy, Seung Hoi Koo

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

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 PKCε 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.

Original languageEnglish
Pages (from-to)240-251
Number of pages12
JournalCell Metabolism
Volume9
Issue number3
DOIs
Publication statusPublished - 2009 Mar 4

Keywords

  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Ryu, D., Oh, K. J., Jo, H. Y., Hedrick, S., Kim, Y. N., Hwang, Y. J., Park, T. S., Han, J. S., Choi, C. S., Montminy, M., & Koo, S. H. (2009). TORC2 Regulates Hepatic Insulin Signaling via a Mammalian Phosphatidic Acid Phosphatase, LIPIN1. Cell Metabolism, 9(3), 240-251. https://doi.org/10.1016/j.cmet.2009.01.007