60
Views
3
CrossRef citations to date
0
Altmetric
Review

Actions and interactions of AMPK with insulin, the peroxisomal-proliferator activated receptors and sirtuins

, , &
Pages 191-208 | Published online: 10 Jan 2014

References

  • Pessin JE, Saltiel AR. Signaling pathways in insulin action: molecular targets of insulin resistance. J. Clin. Invest.106(2), 165–169 (2000).
  • Zammit VA. Role of insulin in hepatic fatty acid partitioning: emerging concepts. Biochem. J.314, 1–14 (1996).
  • Rennie MJ. Exercise- and nutrient-controlled mechanisms involved in maintenance of the musculoskeletal mass. Biochem. Soc. Trans.35, 1302–1305 (2007).
  • Shulman GI. Cellular mechanisms of insulin resistance. J. Clin. Invest106(2), 171–176 (2000).
  • Cooney GJ, Thompson AL, Furler SM, Ye J, Kraegen EW. Muscle long-chain acyl CoA esters and insulin resistance. Ann. NY Acad. Sci.967, 196–207 (2002).
  • Sugden MC, Holness MJ. Role of nuclear receptors in the modulation of insulin secretion in lipid-induced insulin resistance. Biochem. Soc. Trans.36, 891–900 (2008).
  • Yang J, Chi Y, Burkhardt BR, Guan Y, Wolf BA. Leucine metabolism in regulation of insulin secretion from pancreatic beta cells. Nutr. Rev.68(5), 270–279 (2010).
  • Jitrapakdee S, Wutthisathapornchai A, Wallace JC, MacDonald MJ. Regulation of insulin secretion: role of mitochondrial signalling. Diabetologia53(6), 1019–1032 (2010).
  • Sugden MC, Caton PW, Holness MJ. PPAR control: it’s SIRTainly as easy as PGC. J. Endocrinol.204(2), 93–104 (2010).
  • Oakhill JS, Steel R, Chen ZP et al. AMPK is a direct adenylate charge-regulated protein kinase. Science332(6036), 1433–1435 (2011).
  • Carling D, Mayer FV, Sanders MJ, Gamblin SJ. AMP-activated protein kinase: nature’s energy sensor. Nat. Chem. Biol.7(8), 512–518 (2011).
  • Mayer FV, Heath R, Underwood E et al. ADP regulates SNF1, the Saccharomyces cerevisiae homolog of AMP-activated protein kinase. Cell Metab.14(5), 707–714 (2011).
  • Steinberg GR, Kemp BE. AMPK in health and disease. Physiol. Rev.89(3), 1025–1078 (2009).
  • Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev.25(18), 1895–1908 (2011).
  • Oakhill JS, Chen ZP, Scott JW et al. Beta-subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc. Natl Acad. Sci. USA107(45), 19237–19241 (2010).
  • Lizcano JM, Goransson O, Toth R et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J.23(4), 833–843 (2004).
  • Alessi DR, Sakamoto K, Bayascas JR. LKB1-dependent signaling pathways. Annu. Rev. Biochem.75, 137–163 (2006).
  • Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ. Res.100(3), 328–341 (2007).
  • Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J. Biol. Chem.283(41), 27628–27635 (2008).
  • Fulco M, Cen Y, Zhao P et al. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev. Cell14(5), 661–673 (2008).
  • Pillai VB, Sundaresan NR, Kim G et al. Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3–LKB1–AMP-activated kinase pathway. J. Biol. Chem.285(5), 3133–3144 (2010).
  • Gledhill JR, Montgomery MG, Leslie AG, Walker JE. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc. Natl Acad. Sci. USA104(34), 13632–13637 (2007).
  • Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J. Clin. Invest116(7), 1776–1783 (2006).
  • Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem. J.403(1), 139–148 (2007).
  • Voss M, Paterson J, Kelsall IR et al. Ppm1E is an in cellulo AMP-activated protein kinase phosphatase. Cell Signal.23(1), 114–124 (2011).
  • Garcia-Haro L, Garcia-Gimeno MA, Neumann D, Beullens M, Bollen M, Sanz P. The PP1-R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 beta cells. FASEB J.24(12), 5080–5091 (2010).
  • Pan DA, Lillioja S, Kriketos AD et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes46(6), 983–988 (1997).
  • Krssak M, Falk PK, Dresner A et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia42(1), 113–116 (1999).
  • Kautzky-Willer A, Krssak M, Winzer C et al. Increased intramyocellular lipid concentration identifies impaired glucose metabolism in women with previous gestational diabetes. Diabetes52(2), 244–251 (2003).
  • Frojdo S, Durand C, Molin L et al. Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1. Mol. Cell Endocrinol.335(2), 166–176 (2011).
  • Saha AK, Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB. Insulin resistance due to nutrient excess: is it a consequence of AMPK downregulation? Cell Cycle10(20), 3447–3451 (2011).
  • Richter EA, Ruderman NB. AMPK and the biochemistry of exercise: implications for human health and disease. Biochem. J.418(2), 261–275 (2009).
  • Sakamoto K, Holman GD. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am. J. Physiol. Endocrinol. Metab.295(1), E29–E37 (2008).
  • Rowland AF, Fazakerley DJ, James DE. Mapping insulin/GLUT4 circuitry. Traffic12(6), 672–681 (2011).
  • DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in Type 2 diabetes. Diabetes Care32(Suppl. 2), S157–S163 (2009).
  • Vind BF, Pehmoller C, Treebak JT et al. Impaired insulin-induced site-specific phosphorylation of TBC1 domain family, member 4 (TBC1D4) in skeletal muscle of Type 2 diabetes patients is restored by endurance exercise-training. Diabetologia54(1), 157–167 (2011).
  • Chen S, Murphy J, Toth R, Campbell DG, Morrice NA, Mackintosh C. Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem. J.409(2), 449–459 (2008).
  • Jessen N, An D, Lihn AS et al. Exercise increases TBC1D1 phosphorylation in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab.301(1), E164–E171 (2011).
  • Khayat ZA, Patel N, Klip A. Exercise- and insulin-stimulated muscle glucose transport: distinct mechanisms of regulation. Can. J. Appl. Physiol.27(2), 129–151 (2002).
  • Chiu TT, Jensen TE, Sylow L, Richter EA, Klip A. Rac1 signalling towards GLUT4/glucose uptake in skeletal muscle. Cell Signal.23(10), 1546–1554 (2011).
  • Maarbjerg SJ, Sylow L, Richter EA. Current understanding of increased insulin sensitivity after exercise – emerging candidates. Acta Physiol.202(3), 323–335 (2008).
  • Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J. Appl. Physiol.88(6), 2219–2226 (2000).
  • Ruderman NB, Saha AK, Kraegen EW. Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology144(12), 5166–5171 (2003).
  • Yu X, McCorkle S, Wang M et al. Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition. Diabetologia47(11), 2012–2021 (2004).
  • Kim JE, Kim YW, Lee IK et al. AMP-activated protein kinase activation by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) inhibits palmitate-induced endothelial cell apoptosis through reactive oxygen species suppression. J. Pharmacol. Sci.106(3), 394–403 (2008).
  • Putman CT, Kiricsi M, Pearcey J. AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions. J. Physiol.551(1), 169–178 (2003).
  • Henry BA, Andrews ZB, Rao A, Clarke IJ. Central leptin activates mitochondrial function and increases heat production in skeletal muscle. Endocrinology152(7), 2609–2618 (2011).
  • Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM. Transcriptional regulation of adipogenesis. Genes Dev.14(11), 1293–1307 (2000).
  • Habinowski SA, Witters LA. The effects of AICAR on adipocyte differentiation of 3T3-L1 cells. Biochem. Biophys. Res. Commun.286(5), 852–856 (2001).
  • Dagon Y, Avraham Y, Berry EM. AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2alpha in adipocytes. Biochem. Biophys. Res. Commun.340(1), 43–47 (2006).
  • Kajita K, Mune T, Ikeda T et al. Effect of fasting on PPARgamma and AMPK activity in adipocytes. Diabetes Res. Clin. Pract.81(2), 144–149 (2008).
  • Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science299(5606), 572–574 (2003).
  • Picard F, Kurtev M, Chung N et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature429(6993), 771–776 (2004).
  • Villaret A, Galitzky J, Decaunes P et al. Adipose tissue endothelial cells from obese human subjects: differences among depots in angiogenic, metabolic, and inflammatory gene expression and cellular senescence. Diabetes59(11), 2755–2763 (2010).
  • Rutanen J, Yaluri N, Modi S et al. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes59(4), 829–835 (2010).
  • Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Metformin opposes impaired AMPK and SIRT1 function and deleterious changes in core clock protein expression in white adipose tissue of genetically-obese db/db mice. Diabetes Obes. Metab.13(12), 1097–1104 (2011).
  • Lin F, Ribar TJ, Means AR. The Ca2+/calmodulin-dependent protein kinase kinase, CaMKK2, inhibits preadipocyte differentiation. Endocrinology152(10), 3668–3679 (2011).
  • Christodoulides C, Vidal-Puig A. PPARs and adipocyte function. Mol. Cell Endocrinol.318(1–2), 61–68 (2010).
  • Olivecrona T, Hultin M, Bergö M, Olivecrona G. Lipoprotein lipase: regulation and role in lipoprotein metabolism. Proc. Nutr. Soc.56(2), 723–729 (1997).
  • Schrezenmeir J. Hyperinsulinemia, hyperproinsulinemia and insulin resistance in the metabolic syndrome. Experientia52(5), 426–432 (1996).
  • Maheux P, Azhar S, Kern PA, Chen YD, Reuven GM. Relationship between insulin-mediated glucose disposal and regulation of plasma and adipose tissue lipoprotein lipase. Diabetologia40(7), 850–858 (1997).
  • Reynisdottir S, Angelin B, Langin D et al. Adipose tissue lipoprotein lipase and hormone-sensitive lipase. Contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome. Arterioscler. Thromb. Vasc. Biol.17(10), 2287–2292 (1997).
  • Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev.8(10), 1224–1234 (1994).
  • Daval M, Foufelle F, Ferre P. Functions of AMP-activated protein kinase in adipose tissue. J. Physiol.574(Pt 1), 55–62 (2006).
  • Park H, Kaushik VK, Constant S et al. Coordinate regulation of malonyl-CoA decarboxylase, sn-glycerol-3-phosphate acyltransferase, and acetyl-CoA carboxylase by AMP-activated protein kinase in rat tissues in response to exercise. J. Biol. Chem.277(36), 32571–32577 (2002).
  • Gaidhu MP, Perry RL, Noor F, Ceddia RB. Disruption of AMPKalpha1 signaling prevents AICAR-induced inhibition of AS160/TBC1D4 phosphorylation and glucose uptake in primary rat adipocytes. Mol. Endocrinol.24(7), 1434–1440 (2010).
  • Wijkander J, Landström TR, Manganiello V, Belfrage P, Degerman E. Insulin-induced phosphorylation and activation of phosphodiesterase 3B in rat adipocytes: possible role for protein kinase B but not mitogen-activated protein kinase or p70 S6 kinase. Endocrinology139(1), 219–227 (1998).
  • Kitamura T, Kitamura Y, Kuroda S et al. Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt. Mol. Cell Biol.19(9), 6286–6296 (1999).
  • Gauthier MS, Miyoshi H, Souza SC et al. AMP-activated protein kinase is activated as a consequence of lipolysis in the adipocyte: potential mechanism and physiological relevance. J. Biol. Chem.283(24), 16514–16524 (2008).
  • Birk JB, Wojtaszewski JF. Predominant alpha2/beta2/gamma3 AMPK activation during exercise in human skeletal muscle. J. Physiol.577(Pt 3), 1021–1032 (2006).
  • Steinberg GR. Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exercise. Appl. Physiol. Nutr. Metab.34(3), 315–322 (2009).
  • Ahmadian M, Abbott MJ, Tang T. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab.13(6), 739–748 (2011).
  • Djouder N, Tuerk RD, Suter M et al. PKA phosphorylates and inactivates AMPKalpha to promote efficient lipolysis. EMBO J.29(2), 469–481 (2010).
  • Omar B, Zmuda-Trzebiatowska E, Manganiello V, Göransson O, Degerman E. Regulation of AMP-activated protein kinase by cAMP in adipocytes: roles for phosphodiesterases, protein kinase B, protein kinase A, Epac and lipolysis. Cell Signal.21(5), 760–766 (2009).
  • Soliman GA, Acosta-Jaquez HA, Fingar DC. mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes. Lipids45(12), 1089–1100 (2010).
  • Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. N. Engl. J. Med.322(4), 223–228 (1990).
  • Roach PJ. Glycogen and its metabolism. Curr. Mol. Med.2(2), 101–120 (2002).
  • McManus EJ, Sakamoto K, Armit LJ et al. Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J.24(8), 1571–1583 (2005).
  • Lee J, Kim MS. The role of GSK3 in glucose homeostasis and the development of insulin resistance. Diabetes Res. Clin. Pract.77(Suppl. 1) S49–S57 (2007).
  • Friedman, Larner J. Studies on UDPG-alpha-glucan transglucosylase. III. Interconversion of two forms of muscle UDPG-alpha-glucan transglucosylase by a phosphorylation-dephosphorylation reaction sequence. Biochemistry2669–2675 (1963).
  • Jensen J, Lai YC. Regulation of muscle glycogen synthase phosphorylation and kinetic properties by insulin, exercise, adrenaline and role in insulin resistance. Arch. Physiol. Biochem.115(1), 13–21 (2009).
  • Bouskila M, Hunter RW, Ibrahim AF et al. Allosteric regulation of glycogen synthase controls glycogen synthesis in muscle. Cell Metab.12(5), 456–466 (2010).
  • Hunter RW, Treebak JT, Wojtaszewski JF, Sakamoto K. Molecular mechanism by which AMP-activated protein kinase activation promotes glycogen accumulation in muscle. Diabetes60(3), 766–774 (2011).
  • Luptak I, Shen M, He H et al. Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage. J. Clin. Invest.117(5), 1432–1439 (2007).
  • Marsin AS, Bertrand L, Rider MH et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr. Biol.10(20), 1247–1255 (2000).
  • Zhang L, Keung W, Samokhvalov V, Wang W, Lopaschuk GD. Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle. Biochim. Biophys. Acta1801(1), 1–22 (2010).
  • Russell RR 3rd, Li J, Coven DL et al. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J. Clin. Invest.114(4), 495–503 (2004).
  • Oliveira SM, Ehtisham J, Redwood CS, Ostman-Smith I, Blair EM, Watkins H. Mutation analysis of AMP-activated protein kinase subunits in inherited cardiomyopathies: implications for kinase function and disease pathogenesis. J. Mol. Cell Cardiol.35(10), 1251–1255 (2003).
  • Arad M, Seidman CE, Seidman JG. AMP-activated protein kinase in the heart: role during health and disease. Circ. Res.100(4), 474–488 (2007).
  • Febbraio M, Abumrad NA, Hajjar DP et al. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J. Biol. Chem.274(27), 19055–19062 (1999).
  • Coburn CT, Knapp FF Jr, Febbraio M, Beets AL, Silverstein RL, Abumrad NA. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J. Biol. Chem.275(42), 32523–32529 (2000).
  • Yang J, Sambandam N, Han X et al. CD36 deficiency rescues lipotoxic cardiomyopathy. Circ. Res.100(8), 1208–1217 (2007).
  • Schwenk RW, Holloway GP, Luiken JJ, Bonen A, Glatz JF. Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins Leukot. Essent. Fatty Acids82(4–6), 149–154 (2010).
  • Chiu HC, Kovacs A, Blanton RM et al. Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ. Res.96(2), 225–233 (2005).
  • Chiu HC, Kovacs A, Ford DA et al. A novel mouse model of lipotoxic cardiomyopathy. J. Clin. Invest.107(7), 813–822 (2001).
  • Luiken JJ, Coort SL, Willems J et al. Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling. Diabetes52(7), 1627–1634 (2003).
  • Habets DD, Coumans WA, Voshol PJ et al. AMPK-mediated increase in myocardial long-chain fatty acid uptake critically depends on sarcolemmal CD36. Biochem. Biophys. Res. Commun.355(1), 204–210 (2007).
  • Mashek DG, Coleman RA. Cellular fatty acid uptake: the contribution of metabolism. Curr. Opin. Lipidol.17(3), 274–278 (2006).
  • Coort SL, Hasselbaink DM, Koonen DP et al. Enhanced sarcolemmal FAT/CD36 content and triacylglycerol storage in cardiac myocytes from obese zucker rats. Diabetes53(7), 1655–1663 (2004).
  • Bonen A, Parolin ML, Steinberg GR et al. Triacylglycerol accumulation in human obesity and Type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36. FASEB J.18(10), 1144–1146 (2004).
  • Guillet-Deniau I, Pichard AL, Kone A et al. Glucose induces de novo lipogenesis in rat muscle satellite cells through a sterol-regulatory-element-binding-protein-1c-dependent pathway. J. Cell Sci.117(Pt 10), 1937–1944 (2004).
  • Aas V, Kase ET, Solberg R, Jensen J, Rustan AC. Chronic hyperglycaemia promotes lipogenesis and triacylglycerol accumulation in human skeletal muscle cells. Diabetologia47(8), 1452–1461 (2004).
  • Kakuma T, Lee Y, Higa M et al. Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc. Natl Acad. Sci. USA97(15), 8536–8541 (2000).
  • Park EA, Cook GA. Differential regulation in the heart of mitochondrial carnitine palmitoyltransferase-I muscle and liver isoforms. Mol. Cell Biochem.180(1–2), 27–32 (1998).
  • Sidossis LS, Wolfe RR. Glucose and insulin-induced inhibition of fatty acid oxidation: the glucose-fatty acid cycle reversed. Am. J. Physiol.270(4 Pt 1), E733–E738 (1996).
  • Rasmussen BB, Holmbäck UC, Volpi E, Morio-Liondore B, Paddon-Jones D, Wolfe RR. Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle. J. Clin. Invest.110(11), 1687–1693 (2002).
  • Oakes ND, Furler SM. Evaluation of free fatty acid metabolism in vivo. Ann. NY Acad. Sci.967, 158–175 (2002).
  • Oakes ND, Kjellstedt A, Forsberg GB et al. Development and initial evaluation of a novel method for assessing tissue-specific plasma free fatty acid utilization in vivo using (R)-2-bromopalmitate tracer. J. Lipid Res.40(6), 1155–1169 (1999).
  • Hegarty BD, Cooney GJ, Kraegen EW, Furler SM. Increased efficiency of fatty acid uptake contributes to lipid accumulation in skeletal muscle of high fat-fed insulin-resistant rats. Diabetes51(5), 1477–1484 (2002).
  • Abu-Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G, Wakil SJ. The subcellular localization of acetyl-CoA carboxylase 2. Proc. Natl Acad. Sci. USA97(4), 1444–1449 (2000).
  • Ruderman NB, Saha AK. Metabolic syndrome: adenosine monophosphate-activated protein kinase and malonyl coenzyme A. Obesity14(Suppl.), S125–S133 (2006).
  • Gan Z, Burkart-Hartman EM, Han DH et al. The nuclear receptor PPARbeta/delta programs muscle glucose metabolism in cooperation with AMPK and MEF2. Genes Dev.25(24), 2619–2630 (2011).
  • Lendoye E, Sibille B, Rousseau AS, Murdaca J, Grimaldi PA, Lopez P. PPARbeta activation induces rapid changes of both AMPK subunit expression and AMPK activation in mouse skeletal muscle. Mol. Endocrinol.25(9), 1487–1498 (2011).
  • Serrano-Marco L, Barroso E, El Kochairi I et al. The peroxisome proliferator-activated receptor (PPAR) β/δ agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. Diabetologia55(3), 743-51 (2012).
  • Barroso E, Rodriguez-Calvo R, Serrano-Marco L et al. The PPARbeta/delta activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1alpha-Lipin 1-PPARalpha pathway leading to increased fatty acid oxidation. Endocrinology152(5), 1848–1859 (2011).
  • Mootha VK, Lindgren CM, Eriksson KF et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet.34(3), 267–273 (2003).
  • Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in Type 2 diabetes. Diabetes51(10), 2944–2950 (2002).
  • Lee WJ, Kim M, Park HS et al. AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1. Biochem. Biophys. Res. Commun.340(1), 291–295 (2006).
  • Ruderman NB, Xu XJ, Nelson L et al. AMPK and SIRT1: a long-standing partnership? Am. J. Physiol. Endocrinol. Metab.298(4), E751–E760 (2010).
  • Nisoli E, Tonello C, Cardile A et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science310(5746), 314–317 (2005).
  • Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J. Biol. Chem.280(16), 16456–16460 (2005).
  • Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature434(7029), 113–118 (2005).
  • Canto C, Auwerx J. Calorie restriction: is AMPK a key sensor and effector? Physiology26(4), 214–224 (2011).
  • Canto C, Jiang LQ, Deshmukh AS et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab.11(3), 213–219 (2010).
  • Hirschey MD, Shimazu T, Goetzman E et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature464(7285), 121–125 (2010).
  • Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc. Natl Acad. Sci. USA96(13), 7473–7478 (1999).
  • Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J. Clin. Invest.103(11), 1489–1498 (1999).
  • Hirschey MD, Shimazu T, Jing E et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell44(2), 177–190 (2011).
  • Ahn BH, Kim HS, Song S et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA105(38), 14447–14452 (2008).
  • Jing E, Emanuelli B, Hirschey MD et al. Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc. Natl Acad. Sci. USA108(35), 14608–14613 (2011).
  • Hu X, Xu X, Lu Z et al. AMP activated protein kinase-alpha2 regulates expression of estrogen-related receptor-alpha, a metabolic transcription factor related to heart failure development. Hypertension58(4), 696–703 (2011).
  • Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev.18(16), 1926–1945 (2004).
  • Laplante M, Sabatini DM. mTOR signaling at a glance. J. Cell Sci.122(20), 3589–3594 (2009).
  • Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J. Biol. Chem.285(19), 14071–14077 (2010).
  • Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol. Cell40(2), 310–322 (2010).
  • Wang X, Proud CG. mTORC1 signaling: what we still don’t know. J. Mol. Cell Biol3(4), 206–220 (2011).
  • Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol.12(1), 21–35 (2011).
  • Laplante M, Sabatini DM. An emerging role of mTOR in lipid biosynthesis. Curr. Biol.19(22), R1046–R1052 (2009).
  • Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature468(7327), 1100–1104 (2010).
  • Jung CH, Ro SH, Cao J et al. mTOR regulation of autophagy. FEBS Lett.584(7), 1287–1295 (2010).
  • Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat.Cell Biol.13(9), 1016–1023 (2011).
  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science307(5712), 1098–1101 (2005).
  • Kumar A, Lawrence JC Jr, Jung DY et al. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes59(6), 1397–1406 (2010).
  • Brown EJ, Albers MW, Shin TB et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature369(6483), 756–758 (1994).
  • Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell78(1), 35–43 (1994).
  • Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell136(4), 731–745 (2009).
  • Proud CG. Signalling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem. J.403(2), 217–234 (2007).
  • Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol.10(5), 307–318 (2009).
  • Huang J, Manning BD. The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J.412(2), 179–190 (2008).
  • Roux PP, Shahbazian D, Vu H et al. RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J. Biol. Chem.282(19), 14056–14064 (2007).
  • Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell115(5), 577–590 (2003).
  • Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC Jr. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc. Natl Acad. Sci. USA95(13), 7772–7777 (1998).
  • Navé BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J.344Pt 2, 427–2431 (1999).
  • Sekulic A, Hudson CC, Homme JL et al. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res.60(13), 3504–3513 (2000).
  • Chiang GG, Abraham RT. Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J. Biol. Chem.280(27), 25485–25490 (2005).
  • Holz MK, Blenis J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J. Biol. Chem.280(28), 26089–26093 (2005).
  • Peterson RT, Beal PA, Comb MJ, Schreiber SL. FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J. Biol. Chem.275(10), 7416–7423 (2000).
  • Acosta-Jaquez HA, Keller JA, Foster KG et al. Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth. Mol. Cell Biol.29(15), 4308–4324 (2009).
  • Copp J, Manning G, Hunter T. TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res.69(5), 1821–1827 (2009).
  • Cheng SW, Fryer LG, Carling D, Shepherd PR. Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status. J. Biol. Chem.279(16), 15719–15722 (2004).
  • Ekim B, Magnuson B, Acosta-Jaquez HA, Keller JA, Feener EP, Fingar DC. mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell growth, and cell cycle progression. Mol. Cell Biol.31(14), 2787–2801 (2011).
  • Oshiro N, Takahashi R, Yoshino K et al. The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J. Biol. Chem.282(28), 20329–20339 (2007).
  • Sancak Y, Thoreen CC, Peterson TR et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell25(6), 903–915 (2007).
  • Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol.9(3), 316–323 (2007).
  • Wang L, Harris TE, Lawrence JC Jr. Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J. Biol. Chem.283(23), 15619–15627 (2008).
  • Wang H, Zhang Q, Wen Q et al. Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3K/Akt signaling pathway. Cell Signal.24(1), 17–24 (2012).
  • Jazet IM, Schaart G, Gastaldelli A et al. Loss of 50% of excess weight using a very low energy diet improves insulin-stimulated glucose disposal and skeletal muscle insulin signalling in obese insulin-treated Type 2 diabetic patients. Diabetologia51(2), 309–319 (2008).
  • Dann SG, Selvaraj A, Thomas G. mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol. Med.13(6), 252–259 (2007).
  • Zhang HH, Huang J, Duvel K et al. Insulin stimulates adipogenesis through the Akt–TSC2–mTORC1 pathway. PLoS One4(7), e6189 (2009).
  • Wang L, Lawrence JC Jr, Sturgill TW, Harris TE. Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR. J. Biol. Chem.284(22), 14693–14697 (2009).
  • Carriere A, Romeo Y, Acosta-Jaquez HA et al. ERK1/2 phosphorylate Raptor to promote Ras-dependent activation of mTOR complex 1 (mTORC1). J. Biol. Chem.286(1), 567–577 (2011).
  • Carriere A, Cargnello M, Julien LA et al. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr. Biol.18(17), 1269–1277 (2008).
  • Gwinn DM, Shackelford DB, Egan DF et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell30(2), 214–226 (2008).
  • Sahin E, Colla S, Liesa M et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature470(7334), 359–365 (2011).
  • Topisirovic I, Sonenberg N. 4E-BPs at the crossroads of oncogenic MAPK and AKT signaling. Pigment Cell Melanoma Res.23(5), 585–586 (2010).
  • Tuñón MJ, Sánchez-Campos S, Gutiérrez B, Culebras JM, González-Gallego J. Effects of FK506 and rapamycin on generation of reactive oxygen species, nitric oxide production and nuclear factor kappa B activation in rat hepatocytes. Biochem. Pharmacol.66(3), 439–445 (2003).
  • Kim JH, Chu SC, Gramlich JL et al. Activation of the PI3K/mTOR pathway by BCR–ABL contributes to increased production of reactive oxygen species. Blood105(4), 1717–1723 (2005).
  • Horton LE, Bushell M, Barth-Baus D, Tilleray VJ, Clemens MJ, Hensold JO. p53 activation results in rapid dephosphorylation of the eIF4E-binding protein 4E-BP1, inhibition of ribosomal protein S6 kinase and inhibition of translation initiation. Oncogene21(34), 5325–5334 (2002).
  • Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl Acad. Sci. USA102(23), 8204–8209 (2005).
  • Fontana L, Partridge L, Longo VD. Extending healthy life span – from yeast to humans. Science328(5976), 321–326 (2010).
  • Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature426(6967), 620-(2003).
  • Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development131(16), 3897–3906 (2004).
  • Kaeberlein M, Powers RW 3rd, Steffen KK et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science310(5751), 1193–1196 (2005).
  • Harrison DE, Strong R, Sharp ZD et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature460(7253), 392–395 (2009).
  • Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell6(1), 95–110 (2007).
  • Selman C, Tullet JM, Wieser D et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science326(5949), 140–144 (2009).
  • van Leeuwen I, I, Lain S. Sirtuins and p53. Adv. Cancer Res.102, 171–195 (2009).
  • Cheng HL, Mostoslavsky R, Saito S et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc. Natl Acad. Sci. USA100(19), 10794–10799 (2003).
  • Lin HV, Accili D. Hormonal regulation of hepatic glucose production in health and disease. Cell Metab.14(1), 9–19 (2011).
  • Matsumoto M, Pocai A, Rossetti L, Depinho RA, Accili D. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab.6(3), 208–216 (2007).
  • Foretz M, Viollet B. Regulation of hepatic metabolism by AMPK. J. Hepatol.54(4), 827–829 (2011).
  • Fogarty S, Hardie DG. Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim. Biophys. Acta1804(3), 581–591 (2010).
  • Gillum MP, Erion DM, Shulman GI. Sirtuin-1 regulation of mammalian metabolism. Trends Mol. Med. doi:10.1016/j.molmed.2010.09.005 (2011) (Epub ahead of print).
  • Erion DM, Yonemitsu S, Nie Y et al. Sirt1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Proc. Natl Acad. Sci. USA106(27), 11288–11293 (2009).
  • Zhou G, Myers R, Li Y et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest.108(8), 1167–1174 (2001).
  • Boyle JG, Salt IP, McKay GA. Metformin action on AMP-activated protein kinase: a translational research approach to understanding a potential new therapeutic target. Diabet. Med.27(10), 1097–1106 (2010).
  • Seo E, Park EJ, Joe Y et al. Overexpression of AMPKalpha1 ameliorates fatty liver in hyperlipidemic diabetic rats. Korean J. Physiol. Pharmacol.13(6), 449–454 (2009).
  • Foretz M, Hebrard S, Leclerc J et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest.120(7), 2355–2369 (2010).
  • Takashima M, Ogawa W, Hayashi K et al. Role of KLF15 in regulation of hepatic gluconeogenesis and metformin action. Diabetes59(7), 1608–1615 (2010).
  • Wang RH, Kim HS, Xiao C et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J. Clin. Invest.121(11), 4477–4490 (2011).
  • Li Y, Xu S, Mihaylova MM et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab.13(4), 376–388 (2011).
  • Yecies JL, Zhang HH, Menon S et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab.14(1), 21–32 (2011).
  • Haeusler RA, Accili D. The double life of Irs. Cell Metab.8(1), 7–9 (2008).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.