Molecular Regulators of Metabolism and Cardiometabolic Disease

Indriyanti Rafi Sukmawati, Andi Wijaya


BACKGROUND: The mechanisms that are responsible for energy management in cells in an organism require a complex network of transcription of factors and cofactors.

CONTENT: All living system must maintain a tight equilibrium between energy intake, storage and expenditure for optimal performance. This  tight equilibrium must be both robust and flexible to allow for adaptation to every situation such as exercise or rest and famine or feast. Organisms rely on finely tuned and complex signaling network to confront with all possibilities. Metabolic imbalance can cause dysfunction and pertubation of these networks, which if uncorrected will induce disease such as obesity and diabetes mellitus.

SUMMARY: During the last decades the understanding of the transcriptional regulation of diverse metabolic pathways has contributed to the elucidation of mechanisms of metabolic control and to a better knowledge of the pathogenesis of metabolic diseases.


Full Text:



DeBerardini RJ, Thompson CB. Cellular metabolism and disease: What do metabolic outliers teach us? Cell. 2012; 148: 1132-44, CrossRef.

Cantó C, Auwerx J. PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol. 2009; 20: 98-105, CrossRef.

Chau MDL, Gao J, Yang Q, Wu Z, Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1α pathway. Proc Natl Acad Sci USA. 2010; 107: 12553-8, CrossRef.

Hardie DG. AMP-Activated protein kinase: an energy sensor that regulates all aspects of cellular function. Genes Dev. 2011; 25: 1895-908, CrossRef.

Guarente L. Franklin H. Epstein Lecturer: Sirtuins, aging and medicine. N Eng J Med. 2011; 364: 2235-44, CrossRef.

Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009; 458: 1056-60, CrossRef.

Hardie DG. AMP-activated/SNF1 protein kinases: Conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007; 8: 774-85, CrossRef.

Zhou GC, Myers R, Li Y, Chen YL, Shen XL, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108: 1167-74, CrossRef.

Fryer LGD, Parbu-Patel A, Carling D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem. 2002; 277: 25226-32, CrossRef.

Barnes BR, Long YC, Steiler TL, Leng Y, Galuska D, Wojtaszewski JF, et al. Changes in exercise-induced gene expression in 5'-AMP-activated protein kinase γ3-null and γ3 R225Q transgenic mice. Diabetes. 2005; 54: 3484-9, CrossRef.

Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, et al. AMPK and PPARδ agonists are exercise mimetics. Cell. 2008; 134: 405-15, CrossRef.

Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012; 13: 251-62, CrossRef.

Sakamoto K, McCarthy A, Smith D, Green KA, Hardie DG, Ashworth A, et al. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 2005; 24: 1810-20, CrossRef.

Sakamoto K, Zarrinpashneh E, Budas GR, Pouleur AC, Dutta A, Prescott AR, et al. Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKα2 but not AMPKα1. Am J Physiol Endocrinol Metab. 2006; 290: E780-8, CrossRef.

Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010; 120: 2355-69, CrossRef.

Hardie DG, Carling D, Gamblin SJ. AMP-activated protein kinase: also regulated by ADP?; Trends Biochem Sci. 2011; 36: 470-7, CrossRef.

Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011; 13: 1016-23, CrossRef.

Barnes K, Ingram JC, Porras OH, Barros LF, Hudson ER, Fryer LG, et al. Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK). J Cell Sci. 2002; 115: 2433-42, PMID.

Holmes BF, Kurth-Kraczek EJ, Winder WW. Chronic activation of 59-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J Appl Physiol. 1999; 87: 1990-5, PMID.

Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW. 59-AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes. 1999; 48: 1667-71, CrossRef.

Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol. 2000; 10: 1247-55, CrossRef.

Marsin AS, Bouzin C, Bertrand L, Hue L. The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J Biol Chem. 2002; 277: 30778-83, CrossRef.

Bonen A, Han XX, Habets DD, Febbraio M, Glatz JF, Luiken JJ. A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin and AICAR stimulated fatty acid metabolism. Am J Physiol Endocrinol Metab. 2007; 292: E1740-9, CrossRef.

Hoppe S, Bierhoff H, Cado I, Weber A, Tiebe M, Grummt I, et al. AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply. Proc Natl Acad Sci. 2009. 106: 17781-6, CrossRef.

Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet induced insulin resistance mice. Cell Metab. 2011; 13: 376-88, CrossRef.

Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008; 30: 214-26, CrossRef.

Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011; 12: 21-35, CrossRef.

Lin J, Handschin C, Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005; 1: 361-70, CrossRef.

Jager S, Handschin C, St‑Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc Natl Acad Sci USA. 2007; 104: 12017-22, CrossRef.

Cantó C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 2010; 11: 213-9, CrossRef.

Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009; 458: 1056-60, CrossRef.

Nakagawa T, Guarente L. Sirtuins at a glance. J Cell Sci. 2011; 124: 833-8, CrossRef.

Milne JC, Denu JM. The Sirtuin family: therapeutic targets to treat diseases of aging. Curr Opin Chem Biol. 2008; 12: 11-7, CrossRef.

Donmez G, Guarente L. Aging and disease: connections to sirtuins. Aging Cell. 2010; 9: 285-90, CrossRef.

Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010; 5: 253-95, CrossRef.

Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell. 2007; 28: 91-106, CrossRef.

Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature. 2005; 434: 113-8, CrossRef.

Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004; 116: 551-63, CrossRef.

Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, et al. Stress dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303: 2011-5, CrossRef.

Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK mediated chromatin remodeling and circadian control. Cell. 2008; 134: 329-40, CrossRef.

Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell. 2008; 134: 317-28, CrossRef.

Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPARγ. Nature. 2004; 429: 771-6, CrossRef.

Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005; 310: 314-7, CrossRef.

Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009; 9: 327-38, CrossRef.

Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature. 2008; 456: 269-73, CrossRef.

Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 2012; 13: 225-38, CrossRef.

Schug TT, Li X. Sirtuin 1 in lipid metabolism and obesity. Ann Med. 2011; 43: 198-211, CrossRef.

Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005; 39: 359-407, CrossRef.

Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000; 408: 239-47, CrossRef.

Ryan MT, Hoogenraad NJ. Mitochondrial-nuclear communications. Annu Rev Biochem. 2007; 76: 701-22, CrossRef.

Scarpulla RC. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochem Biophys Acta. 2002; 1576: 1-14, CrossRef.

Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci. 2010; 35: 669-75, CrossRef.

Kaasik K, Lee CC. Reciprocal regulation of haem biosynthesis and the circadian clock in mammals. Nature. 2004; 430: 467-71, CrossRef.

Rutter J, Reick M, McKnight SL. Metabolism and the control of circadian rhythms. Annu Rev Biochem. 2002; 71: 307-31, CrossRef.

Tu BP, McKnight SL. Metabolic cycles as an underlying basis of Biological oscillations. Nat Rev Mol Cell Biol. 2006; 7: 696-701, CrossRef.

Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi, P. Circadian control of the NAD+ salvage pathway by CLOCKSIRT1. Science. 2009; 324: 654-7, CrossRef.

Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, et al. Modulation of NF-ΚB dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004; 23: 2369-80, CrossRef.

Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1α. Mol. Cell. 2010; 38: 864-78, CrossRef.

Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Linet M, et al. SIRT6 links histone H3 lysine 9 deacetylation to NFΚB dependent gene expression and organismal life span. Cell. 2009; 136: 62-74, CrossRef.

Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005; 310: 314-7, CrossRef.

Lefevre M, Redman LM, Heilbronn LK, Smith JV, Martin CK, Rood JC, et al. Caloric restriction alone and with exercise improves CVD risk in healthy non obese individuals. Atherosclerosis. 2009; 203: 206-13, CrossRef.

Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ. Nuclear receptors and lipid physiology: opening the X-files. Science. 2001; 294: 1866-70, CrossRef.

Francis GA, Fayard E, Picard F, Auwerx J. Nuclear receptors and the control of metabolism. Annu Rev Physiol. 2003; 65: 261-311, CrossRef.

Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011; 93: 884S-90S, CrossRef.

Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998; 92: 829-39, CrossRef.

Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator activated receptor α in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000; 20: 1868-76, CrossRef.

Huss JM, Kopp RP, Kelly DP. Peroxisome proliferator activated receptor coactivator 1α (PGC-1α) coactivates the cardiac enriched nuclear receptors estrogen related receptorα and γ: identification of novel leucine-rich interaction motif within PGC-1α. J Biol Chem. 2002; 277: 40265-74, CrossRef.

Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1 PGC 1α interaction. Nature. 2003; 423: 550-5, CrossRef.

Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1α. Nature. 2001; 413: 131-8, CrossRef.

Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1α. Cell. 1999; 98: 115-24, CrossRef.

Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet. 2004; 20: 563-9, CrossRef.

Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol. 2001; 2: S3005, PMID.

Sakaue H, Konishi M, Ogawa W, Asaki T, Mori T, Yamasaki M, et al. Requirement of fibroblast growth factor 10 in development of white adipose tissue. Genes Dev. 2002; 16: 908-12, CrossRef.

Bhushan A, Itoh N, Kato S, Thiery JP, Czernichow P, Bellusci S, et al. FGF10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. Development. 2001; 128: 5109-17, PMID.

Ohuchi H, Hori Y, Yamasaki M, Harada H, Sekine K, Kato S, et al. FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multiorgan development. Biochem Biophys Res Commun. 2000; 277: 643-9, CrossRef.

Konishi M, Micami T, Yamasaki M, Miyake A, Itoh N. Fibroblast growth factor-16 is a growth factor for embryonic brown adipocytes. J Biol Chem. 1999; 255: 12119-22, CrossRef.

Nishimura T, Utsonomiya Y, Hoshikawa M, Ohuchi H, Itoh N. Structure and expression of a novel human FGF, FGF-19, expressed in the fetal brain. Biochim Biophys Acta. 1999; 1444: 148-51, CrossRef.

Xie MH, Holcomb I, Deuel B, Dowd P, Huang A, Vagts A, et al. 1999. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4. Cytokine. 1999; 11: 729-35, CrossRef.

Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology. 2002; 143: 1741-7, CrossRef.

Fu L, John LM, Adams SH, Yu XX, Tomlinson E, Renz M, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin deficient diabetes. Endocrinology. 2004; 145: 2594-603, CrossRef.

Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, et al. Adipose Fibroblast Growth Factor 21 Is Up-Regulated by Peroxisome Proliferator-Activated Receptor γ and Altered Metabolic States. Mol Pharmacol. 2008; 74: 403-12, CrossRef.

Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007; 5: 426-37, CrossRef.

Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 2007; 5: 415-25, CrossRef.

Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, et al. FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA. 2009; 106: 10853-8, CrossRef.

Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell. 2012; 148: 556-67, CrossRef.

Oishi K, Konishi M, Murata Y, Itoh N. Time-imposed daily restricted feeding induces rhythmic expression of Fgf21 in white adipose tissue of mice. Biochem Biophys Res Commun. 2011; 412: 396-400, CrossRef.

Wang H, Qiang L, Farmer SR. Identification of a domain within peroxisome proliferator-activated receptor α regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol Cell Biol. 2008; 28: 188-200, CrossRef.

Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005; 115: 1627-35, CrossRef.

Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. FGF21 regulates PGC-α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012; 26: 271-81, CrossRef.

Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F. Hepatic FGF21 expression is induced at birth via PPARα in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 2010; 11: 206-12, CrossRef.

Cantó C, Auwerx J. Cell biology. FGF21 takes a fat bite. Science. 2012; 336: 675-6, CrossRef.

Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008; 454: 961-7, CrossRef.

Lepper C, Fan CM. Inducible lineage tracing of Pax7 descendant cells reveals embryonic origin of adult satellite cells. Genesis. 2010; 48: 424-36, CrossRef.

Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Penicaud L, et al. Occurrence of brown adipocytes in rat white adipose tissue: Molecular and morphological characterization. J Cell Sci. 1992; 103: 931-42, PMID.

Ghorbani M, Himms-Hagen J. Appearance of brown adipocytes in white adipose tissue during CL 316,243-induced reversal of obesity and diabetes in Zucker fa/fa rats. Int J Obes Relat Metab Disord. 1997; 21: 465-75, CrossRef.

Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, et al. The emergence of cold induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab. 2010; 298: E1244-53, CrossRef.

Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator activated receptor γ (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem. 2010; 285: 7153-64, CrossRef.

Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011; 121: 96-105, CrossRef.

Gälman C, Lundåsen T, Kharitonenkov A, Bina HA, Eriksson M,Hafström I, et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab. 2008; 8: 169-74, CrossRef.

Chen WW, Li L, Yang GY, Li K, Qi XY, Zhu W, et al. Circulating FGF-21 levels in normal subjects and in newly diagnosed patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2008; 116: 65-8, CrossRef.

Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, et al. Obesity is a fibroblast growth factor 21 (FGF21) resistant state. Diabetes. 2010; 59: 2781-9, CrossRef.

Hale C, Chen MM, Stanislaus S, Chinookoswong N, Hager T, Wang M, et al. Lack of overt FGF21 resistance in two mouse models of obesity and insulin resistance. Endocrinology. 2012; 153: 69-80, CrossRef.

Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, et al. Hypothalamic mTOR signaling regulates food intake. Science. 2006; 312: 927-30, CrossRef.

Ropelle ER, Pauli JR, Fernandes MF, Rocco SA, Marin RM, Morari J, et al. A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in high protein diet induced weight loss. Diabetes. 2008; 57: 594-605, CrossRef.

Morrison CD, Xi X, White CL, Ye J, Martin RJ. Amino acids inhibit Agrp gene expression via an mTOR dependent mechanism. Am J Physiol Endocrinol Metab. 2007; 293: E165-71, CrossRef.

Catania C, Binder E, Cota D. mTORC1 signaling in energy balance and metabolic disease. Int J Obes (Lond). 2011; 35: 751-61, CrossRef.

Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006; 124: 471-84, CrossRef.

Dennis PB, Jaeschke A, Saitoh M, Fowler B, Kozma SC, Thomas G. Mammalian TOR: a homeostatic ATP sensor. Science. 2001; 294: 1102-5, CrossRef.

Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest. 2006; 116: 1761-6, CrossRef.

Hornberger TA, Chien S. Mechanical stimuli and nutrients regulate rapamycin sensitive signaling through distinct mechanisms in skeletal muscle. J Cell Biochem. 2006; 97: 1207-16, CrossRef.

Rivas DA, Lessard SJ, Coffey VG. mTOR function in skeletal muscle: a focal point for overnutrition and exercise. Appl Physiol Nutr Metab. 2009; 34: 807-16, CrossRef.

Tremblay F, Jacques H, Marette A. Modulation of insulin action by dietary proteins and amino acids: role of the mammalian target of rapamycin nutrient sensing pathway. Curr Opin Clin Nutr Metab Care. 2005; 8: 457-62, CrossRef.

Laplante M, Sabatini DM. An emerging role of mTOR in lipid biosynthesis. Curr Biol. 2009; 19: R1046-52, CrossRef.

Zhang HH, Huang J, Duvel K, Boback B, Wu S, Squillace RM, et al. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLoS ONE. 2009; 4: e6189, CrossRef.

Chakrabarti P, English T, Shi J, Smas CM, Kandror KV. The mTOR complex 1 suppresses lipolysis, stimulates lipogenesis and promotes fat storage. Diabetes. 2010; 59: 775-81, CrossRef.

Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, et al. Absence of S6K1 protects against age and diet induced obesity while enhancing insulin sensitivity. Nature. 2004; 431: 200-5, CrossRef.

Rachdi L, Balcazar N, Osorio-Duque F, Elghazi L, Weiss A, Gould A, et al. Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1-dependent manner. Proc Natl Acad Sci USA. 2008; 105: 9250-5, CrossRef.

Fu A, Ng AC, Depatie C, Wijesekara N, He Y, Wang GS, et al. Loss of Lkb1 in adult beta cells increases beta cell mass and enhances glucose tolerance in mice. Cell Metab. 2009; 10: 285-95, CrossRef.

Zahr E, Molano RD, Pileggi A, Ichii H, San Jose S, Bocca N, et al. Rapamycin impairs beta cell proliferation in vivo. Transplant Proc. 2008; 40: 436-7, CrossRef.

Azzariti A, Porcelli L, Gatti G, Nicolin A, Paradiso A. Synergic antiproliferative and antiangiogenic effects of EGFR and mTor inhibitors on pancreatic cancer cells. Biochem Pharmacol. 2008; 75: 1035-44, CrossRef.

Fraenkel M, Ketzinel-Gilad M, Ariav Y, Pappo O, Karaca M, Castel J, et al. mTOR inhibition by rapamycin prevents β cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes. 2008; 57: 945-57, CrossRef.

Chang GR, Wu YY, Chiu YS, Chen WY, Liao JW, Hsu HM, et al. Long term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice. Basic Clin Pharmacol Toxicol. 2009; 105: 188-98, CrossRef.

Chen P, Yan H, Chen Y, He Z. The variation of AkT/TSC1-TSC1/mTOR signal pathway in hepatocytes after partial hepatectomy in rats. Exp Mol Pathol. 2009; 86: 101-7, CrossRef.

Chotechuang N, Azzout-Marniche D, Bos C, Chaumontet C, Gausseres N, Steiler T, et al. mTOR, AMPK, and GCN2 coordinate the adaptation of hepatic energy metabolic pathways in response to protein intake in the rat. Am J Physiol Endocrinol Metab. 2009; 297: E1313-23, CrossRef.

Hamada S, Hara K, Hamada T, Yasuda H, Moriyama H, Nakayama R, et al. Upregulation of the mammalian target of rapamycin complex 1 pathway by Ras homolog enriched in brain in pancreatic beta cells leads to increased β cell mass and prevention of hyperglycemia. Diabetes. 2009; 58: 1321-32, CrossRef.

Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 2006; 295: 1539-48, CrossRef.

Larson-Meyer DE, Newcomer BR, Heilbronn LK, Volaufova J, Smith SR, Alfonso AJ, et al. Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function. Obesity. 2008; 16: 1355-62, CrossRef.

Lim EL, Hollingsworth KG, Aribisala BS, Chen MJ, Mathers JC, Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia 2011; 54: 2506-14, CrossRef.

Canto´C,Auwerx J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab. 2009; 20: 325-31, CrossRef.

Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood J.G, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003; 425: 191-6, CrossRef.

Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des. 2009; 74: 619-24, CrossRef.

Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, et al. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem. 2010; 285: 8340-51, CrossRef.

Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006; 444: 337-42, CrossRef.

Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, et al. Specific SIRT1 activation mimics low energy levels and protects against diet induced metabolic disorders by enhancing fat oxidation. Cell Metab. 2008; 8: 347-58, CrossRef.

Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, et al. Use of cells expressing gamma subunit variants to identify diversemechanisms of AMPK activation. Cell Metab. 2010; 11: 554-65, CrossRef.

Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, et al. AMP-activated protein kinase deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2010; 59: 554-63, CrossRef.

Timmers S, Konings E, Bilet L, Houtkooper RH, Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011; 14: 612-22, CrossRef.

Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 2012; 13: 213-24, CrossRef.


Copyright (c) 2012 The Prodia Education and Research Institute

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.


Indexed by:






The Prodia Education and Research Institute