The Combined Deletion of S6K1 and Akt2 Deteriorates Glycemic Control in a High-Fat Diet

ABSTRACT Signaling downstream of mechanistic target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) controls specific and distinct aspects of insulin action and nutrient homeostasis in an interconnected and as yet unclear way. Mice lacking the mTORC1 substrate S6 kinase 1 (S6K1) maintain proper glycemic control with a high-fat diet. This phenotype is accompanied by insulin hypersensitivity, Akt- and AMP-activated kinase upregulation, and increased lipolysis in adipose tissue and skeletal muscle. Here, we show that, when S6K1 inactivation is combined with the deletion of the mTORC2 substrate Akt2, glucose homeostasis is compromised due to defects in both insulin action and β-cell function. After a high-fat diet, the S6K1−/− Akt2−/− double-mutant mice do not become obese, though they are severely hyperglycemic. Our data demonstrate that S6K1 is required for pancreatic β-cell growth and function during adaptation to insulin resistance states. Strikingly, the inactivation of two targets of mTOR and phosphatidylinositol 3-kinase signaling is sufficient to reproduce major hallmarks of type 2 diabetes.

[1]  Dudley Lamming,et al.  Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity , 2012, Science.

[2]  C. Kahn,et al.  Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1 , 2012, Nature Medicine.

[3]  M. Birnbaum,et al.  PPARγ contributes to PKM2 and HK2 expression in fatty liver , 2012, Nature Communications.

[4]  Y. Jan,et al.  Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity , 2011, Journal of Molecular Medicine.

[5]  J. Albrecht,et al.  S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy. , 2011, The Journal of clinical investigation.

[6]  B. Spiegelman,et al.  Separation of the gluconeogenic and mitochondrial functions of PGC-1{alpha} through S6 kinase. , 2011, Genes & development.

[7]  D. Sabatini,et al.  mTOR: from growth signal integration to cancer, diabetes and ageing , 2010, Nature Reviews Molecular Cell Biology.

[8]  Gregory J Morton,et al.  Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice , 2010, Disease Models & Mechanisms.

[9]  N. Sonenberg,et al.  S6K1 plays a critical role in early adipocyte differentiation. , 2010, Developmental cell.

[10]  Y. Deshaies,et al.  Chronic Rapamycin Treatment Causes Glucose Intolerance and Hyperlipidemia by Upregulating Hepatic Gluconeogenesis and Impairing Lipid Deposition in Adipose Tissue , 2010, Diabetes.

[11]  J. Downward,et al.  Rictor is a novel target of p70 S6 kinase-1 , 2010, Oncogene.

[12]  Philippe P Roux,et al.  mTORC1-Activated S6K1 Phosphorylates Rictor on Threonine 1135 and Regulates mTORC2 Signaling , 2009, Molecular and Cellular Biology.

[13]  Janet M. Thornton,et al.  Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span , 2009, Science.

[14]  J. Asara,et al.  Characterization of Rictor Phosphorylation Sites Reveals Direct Regulation of mTOR Complex 2 by S6K1 , 2009, Molecular and Cellular Biology.

[15]  Marco Pahor,et al.  Rapamycin fed late in life extends lifespan in genetically heterogeneous mice , 2009, Nature.

[16]  J. Rovira,et al.  Mammalian target of rapamycin and diabetes: what does the current evidence tell us? , 2009, Transplantation proceedings.

[17]  S. Germain,et al.  Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation. , 2008, The Journal of clinical investigation.

[18]  Christophe Magnan,et al.  mTOR Inhibition by Rapamycin Prevents β-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes , 2008, Diabetes.

[19]  S. R. Datta,et al.  Dual role of proapoptotic BAD in insulin secretion and beta cell survival , 2008, Nature Medicine.

[20]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[21]  P. Bénit,et al.  S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase. , 2007, Cell metabolism.

[22]  D. Befroy,et al.  Aging-Associated Reductions in AMP-Activated Protein Kinase Activity and Mitochondrial Biogenesis , 2007, Cell metabolism.

[23]  P. Kapahi,et al.  Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans , 2007, Aging cell.

[24]  Tony Hunter,et al.  Turnover of the Active Fraction of IRS1 Involves Raptor-mTOR- and S6K1-Dependent Serine Phosphorylation in Cell Culture Models of Tuberous Sclerosis , 2006, Molecular and Cellular Biology.

[25]  D. Sabatini,et al.  Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. , 2006, Molecular cell.

[26]  C. Kahn,et al.  Critical nodes in signalling pathways: insights into insulin action , 2006, Nature Reviews Molecular Cell Biology.

[27]  Yuval Dor,et al.  Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. , 2005, Genes & development.

[28]  J. Blenis,et al.  Identification of S6 Kinase 1 as a Novel Mammalian Target of Rapamycin (mTOR)-phosphorylating Kinase* , 2005, Journal of Biological Chemistry.

[29]  N. Sonenberg,et al.  Atrophy of S6K1−/− skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control , 2005, Nature Cell Biology.

[30]  Johan Auwerx,et al.  Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity , 2004, Nature.

[31]  I. Gout,et al.  The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins , 2004, The Journal of cell biology.

[32]  P. Puigserver,et al.  Suppression of β Cell Energy Metabolism and Insulin Release by PGC-1α , 2003 .

[33]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[34]  M. Mann,et al.  p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  K. Kaestner,et al.  Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ) , 2001 .

[36]  R. Burcelin,et al.  Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice , 2000, Nature.

[37]  C. Kahn,et al.  Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. , 2000, Molecular cell.

[38]  Stefano Fumagalli,et al.  Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase , 1998, The EMBO journal.

[39]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[40]  D. Sabatini,et al.  mTOR Signaling. , 2012, Cold Spring Harbor perspectives in biology.

[41]  P. Puigserver,et al.  Suppression of beta cell energy metabolism and insulin release by PGC-1alpha. , 2003, Developmental cell.

[42]  K. Kaestner,et al.  Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). , 2001, Science.