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Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism.


ABSTRACT:

Objective

Rictor is an essential component of mammalian target of rapamycin (mTOR) complex (mTORC) 2, a kinase that phosphorylates and activates Akt, an insulin signaling intermediary that regulates glucose and lipid metabolism in adipose tissue, skeletal muscle, and liver. To determine the physiological role of rictor/mTORC2 in insulin signaling and action in fat cells, we developed fat cell-specific rictor knockout (FRic(-/-)) mice.

Research design and methods

Insulin signaling and glucose and lipid metabolism were studied in FRic(-/-) fat cells. In vivo glucose metabolism was evaluated by hyperinsulinemic-euglycemic clamp.

Results

Loss of rictor in fat cells prevents insulin-stimulated phosphorylation of Akt at S473, which, in turn, impairs the phosphorylation of downstream targets such as FoxO3a at T32 and AS160 at T642. However, glycogen synthase kinase-3beta phosphorylation at S9 is not affected. The signaling defects in FRic(-/-) fat cells lead to impaired insulin-stimulated GLUT4 translocation to the plasma membrane and decreased glucose transport. Furthermore, rictor-null fat cells are unable to suppress lipolysis in response to insulin, leading to elevated circulating free fatty acids and glycerol. These metabolic perturbations are likely to account for defects observed at the whole-body level of FRic(-/-) mice, including glucose intolerance, marked hyperinsulinemia, insulin resistance in skeletal muscle and liver, and hepatic steatosis.

Conclusions

Rictor/mTORC2 in fat cells plays an important role in whole-body energy homeostasis by mediating signaling necessary for the regulation of glucose and lipid metabolism in fat cells.

SUBMITTER: Kumar A 

PROVIDER: S-EPMC2874700 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Publications

Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism.

Kumar Anil A   Lawrence John C JC   Jung Dae Young DY   Ko Hwi Jin HJ   Keller Susanna R SR   Kim Jason K JK   Magnuson Mark A MA   Harris Thurl E TE  

Diabetes 20100323 6


<h4>Objective</h4>Rictor is an essential component of mammalian target of rapamycin (mTOR) complex (mTORC) 2, a kinase that phosphorylates and activates Akt, an insulin signaling intermediary that regulates glucose and lipid metabolism in adipose tissue, skeletal muscle, and liver. To determine the physiological role of rictor/mTORC2 in insulin signaling and action in fat cells, we developed fat cell-specific rictor knockout (FRic(-/-)) mice.<h4>Research design and methods</h4>Insulin signaling  ...[more]

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