Sestrin 3 protein enhances hepatic insulin sensitivity by direct activation of the mTORC2-Akt signaling

Rongya Tao, Xiwen Xiong, Suthat Liangpunsakul, X. Dong

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Sestrin proteins have been implicated in multiple biological processes including resistance to oxidative and genotoxic stresses, protection against agingrelated pathologies, and promotion of metabolic homeostasis; however, the underlying mechanisms are incompletely understood. Some evidence suggests that sestrins may inhibit mTORC1 (mechanistic target of rapamycin complex 1) through inhibition of RagA/B GTPases or activation of AMPK; however, whether sestrins are also involved in mTORC2 regulation and function is unclear. To investigate the functions and mechanisms of Sestrin 3 (Sesn3), we generated Sesn3 liver-specific transgenic and knockout mice. Our data show that Sesn3 liver-specific knockout mice exhibit insulin resistance and glucose intolerance, and Sesn3 transgenic mice were protected against insulin resistance induced by a high-fat diet. Using AMPK liverspecific knockout mice, we demonstrate that the Sesn3 insulin-sensitizing effect is largely independent of AMPK. Biochemical analysis reveals that Sesn3 interacts with and activates mTORC2 and subsequently stimulates Akt phosphorylation at Ser473. These findings suggest that Sesn3 can activate Akt via mTORC2 to regulate hepatic insulin sensitivity and glucose metabolism.

Original languageEnglish (US)
Pages (from-to)1211-1223
Number of pages13
JournalDiabetes
Volume64
Issue number4
DOIs
StatePublished - Apr 1 2015

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AMP-Activated Protein Kinases
Knockout Mice
Insulin Resistance
Transgenic Mice
Liver
Biological Phenomena
Proteins
Glucose Intolerance
GTP Phosphohydrolases
High Fat Diet
DNA Damage
Oxidative Stress
Homeostasis
Phosphorylation
Insulin
Pathology
Glucose
TOR complex 2

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Sestrin 3 protein enhances hepatic insulin sensitivity by direct activation of the mTORC2-Akt signaling. / Tao, Rongya; Xiong, Xiwen; Liangpunsakul, Suthat; Dong, X.

In: Diabetes, Vol. 64, No. 4, 01.04.2015, p. 1211-1223.

Research output: Contribution to journalArticle

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AU - Dong, X.

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AB - Sestrin proteins have been implicated in multiple biological processes including resistance to oxidative and genotoxic stresses, protection against agingrelated pathologies, and promotion of metabolic homeostasis; however, the underlying mechanisms are incompletely understood. Some evidence suggests that sestrins may inhibit mTORC1 (mechanistic target of rapamycin complex 1) through inhibition of RagA/B GTPases or activation of AMPK; however, whether sestrins are also involved in mTORC2 regulation and function is unclear. To investigate the functions and mechanisms of Sestrin 3 (Sesn3), we generated Sesn3 liver-specific transgenic and knockout mice. Our data show that Sesn3 liver-specific knockout mice exhibit insulin resistance and glucose intolerance, and Sesn3 transgenic mice were protected against insulin resistance induced by a high-fat diet. Using AMPK liverspecific knockout mice, we demonstrate that the Sesn3 insulin-sensitizing effect is largely independent of AMPK. Biochemical analysis reveals that Sesn3 interacts with and activates mTORC2 and subsequently stimulates Akt phosphorylation at Ser473. These findings suggest that Sesn3 can activate Akt via mTORC2 to regulate hepatic insulin sensitivity and glucose metabolism.

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