Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling

Chongben Zhang, Angela A. Wendel, Matthew R. Keogh, Thurl E. Harris, Jie Chen, Rosalind A. Coleman

Research output: Contribution to journalArticle

Abstract

Increased flux through the glycerolipid synthesis pathway impairs the ability of insulin to inhibit hepatic gluconeogenesis, but the exact mechanism remains unknown. To determine the mechanism by which glycerolipids impair insulin signaling, we overexpressed glycerol-3-phosphate acyltransferase-1 (GPAT1) in primary mouse hepatocytes. GPAT1 overexpression impaired insulin-stimulated phosphorylation of Akt-S473 and -T308, diminished insulin-suppression of glucose production, significantly inhibited mTOR complex 2 (mTORC2) activity and decreased the association of mTOR and rictor. Conversely, in hepatocytes from Gpat1 -/- mice, mTOR-rictor association and mTORC2 activity were enhanced. However, this increase in mTORC2 activity in Gpat1 -/- hepatocytes was ablated when rictor was knocked down. To determine which lipid intermediate was responsible for inactivating mTORC2, we overexpressed GPAT1, AGPAT, or lipin to increase the cellular content of lysophosphatidic acid (LPA), phosphatidic acid (PA), or diacylglycerol (DAG), respectively. The inhibition of mTOR/rictor binding and mTORC2 activity coincided with the levels of PA and DAG species that contained 16:0, the preferred substrate of GPAT1. Furthermore, di-16:0-PA strongly inhibited mTORC2 activity and disassociated mTOR/rictor in vitro. Taken together, these data reveal a signaling pathway by which phosphatidic acid synthesized via the glycerol-3-phosphate pathway inhibits mTORC2 activity by decreasing the association of rictor and mTOR, thereby down-regulating insulin action. These data demonstrate a critical link between nutrient excess, TAG synthesis, and hepatic insulin resistance.

Original languageEnglish (US)
Pages (from-to)1667-1672
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number5
DOIs
StatePublished - Jan 31 2012

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Acyltransferases
Phosphatidic Acids
Insulin
Hepatocytes
Diglycerides
Gluconeogenesis
Liver
Insulin Resistance
Phosphorylation
alpha-glycerophosphoric acid
Lipids
Glucose
Food

Keywords

  • Hepatic steatosis
  • Palmitate
  • Triacylglycerol

ASJC Scopus subject areas

  • General

Cite this

Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling. / Zhang, Chongben; Wendel, Angela A.; Keogh, Matthew R.; Harris, Thurl E.; Chen, Jie; Coleman, Rosalind A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 5, 31.01.2012, p. 1667-1672.

Research output: Contribution to journalArticle

Zhang, Chongben ; Wendel, Angela A. ; Keogh, Matthew R. ; Harris, Thurl E. ; Chen, Jie ; Coleman, Rosalind A. / Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 5. pp. 1667-1672.
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