Abstract
Mammalian target of rapamycin complex 2 (mTORC2) is a key activator of protein kinases that act downstream of insulin and growth factor signaling. Here we report that mice lacking the essential mTORC2 component rictor in liver (Lrictor(KO)) are unable to respond normally to insulin. In response to insulin, Lrictor(KO) mice failed to inhibit hepatic glucose output. Lrictor(KO) mice also fail to develop hepatic steatosis on a high fat diet and manifest half-normal serum cholesterol levels. This is accompanied by lower levels of expression of SREBP-1c and SREBP-2 and genes of fatty acid and cholesterol biosynthesis. Lrictor(KO) mice had defects in insulin-stimulated Akt Ser-473 and Thr-308 phosphorylation, leading to decreased phosphorylation of Akt substrates FoxO, GSK-3β, PRAS40, AS160, and Tsc2. Lrictor(KO) mice also manifest defects in insulin-activated mTORC1 activity, evidenced by decreased S6 kinase and Lipin1 phosphorylation. Glucose intolerance and insulin resistance of Lrictor(KO) mice could be fully rescued by hepatic expression of activated Akt2 or dominant negative FoxO1. However, in the absence of mTORC2, forced Akt2 activation was unable to drive hepatic lipogenesis. Thus, we have identified an Akt-independent relay from mTORC2 to hepatic lipogenesis that separates the effects of insulin on glucose and lipid metabolism.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / metabolism
-
Animals
-
Cholesterol / biosynthesis
-
Cholesterol / genetics
-
Fatty Acids / genetics
-
Fatty Acids / metabolism
-
Forkhead Box Protein O1
-
Forkhead Transcription Factors / genetics
-
Forkhead Transcription Factors / metabolism
-
GTPase-Activating Proteins / genetics
-
GTPase-Activating Proteins / metabolism
-
Gene Expression Regulation / physiology
-
Glucose / genetics
-
Glucose / metabolism
-
Glycogen Synthase Kinase 3 / genetics
-
Glycogen Synthase Kinase 3 / metabolism
-
Glycogen Synthase Kinase 3 beta
-
Hep G2 Cells
-
Humans
-
Insulin / genetics
-
Insulin / metabolism
-
Insulin Resistance / physiology
-
Lipogenesis / physiology*
-
Liver / metabolism*
-
Mice
-
Mice, Transgenic
-
Phosphoproteins / genetics
-
Phosphoproteins / metabolism
-
Phosphorylation / physiology
-
Proto-Oncogene Proteins c-akt / genetics
-
Proto-Oncogene Proteins c-akt / metabolism*
-
Sterol Regulatory Element Binding Protein 1 / genetics
-
Sterol Regulatory Element Binding Protein 1 / metabolism
-
Sterol Regulatory Element Binding Protein 2 / genetics
-
Sterol Regulatory Element Binding Protein 2 / metabolism
-
Trans-Activators / genetics
-
Trans-Activators / metabolism*
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Tuberous Sclerosis Complex 2 Protein
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism
Substances
-
AKT1S1 protein, human
-
Adaptor Proteins, Signal Transducing
-
CRTC2 protein, human
-
Crtc2 protein, mouse
-
FOXO1 protein, human
-
Fatty Acids
-
Forkhead Box Protein O1
-
Forkhead Transcription Factors
-
Foxo1 protein, mouse
-
GTPase-Activating Proteins
-
Insulin
-
Phosphoproteins
-
SREBF1 protein, human
-
SREBF2 protein, human
-
Srebf1 protein, mouse
-
Srebf2 protein, mouse
-
Sterol Regulatory Element Binding Protein 1
-
Sterol Regulatory Element Binding Protein 2
-
TBC1D4 protein, human
-
TSC2 protein, human
-
Tbc1d4 protein, mouse
-
Trans-Activators
-
Transcription Factors
-
Tsc2 protein, mouse
-
Tuberous Sclerosis Complex 2 Protein
-
Tumor Suppressor Proteins
-
proline-rich Akt substrate, 40 kDa protein, mouse
-
Cholesterol
-
AKT2 protein, human
-
Akt2 protein, mouse
-
GSK3B protein, human
-
Glycogen Synthase Kinase 3 beta
-
Gsk3b protein, mouse
-
Proto-Oncogene Proteins c-akt
-
Glycogen Synthase Kinase 3
-
Glucose