Sestrin 3 protein enhances hepatic insulin sensitivity by direct activation of the mTORC2-Akt signaling.
Sestrin proteins have been implicated in multiple biological processes including resistance to oxidative and genotoxic stresses, protection against aging-related 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 liver-specific 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.
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.
Rongya
R
Tao
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.
Xiwen
X
Xiong
Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Roudebush Veterans Administration Medical Center, Indianapolis, IN.
Suthat
S
Liangpunsakul
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN xcdong@iu.edu.
X Charlie
XC
Dong
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000084622:Sestrins
D000263:Adenylate Kinase; D005947:Glucose; D006360:Heat-Shock Proteins; D007328:Insulin; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C549101:Sesn3 protein, mouse; D000084622:Sestrins