Targeting mitochondrial biogenesis to treat insulin resistance

Current Pharmaceutical Design

Volumn 20, Issue 35, 2014, Pages 5527-5557

  Zamora, Mònica ^a,b   Villena, Josep A ^c,d  

^a UNIVERSITAT POMPEU FABRA   (Spain)

^b CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED SOBRE ENFERMEDADES NEURODEGENERATIVAS CIBERNED   (Spain)

^c UNIVERSITAT AUTÒNOMA DE BARCELONA   (Spain)

^d INSTITUTO DE SALUD CARLOS III   (Spain)

Author keywords

AMPK; Calorie restriction; Exercise; Mitochondrial dysfunction; PGC 1; SIRT1; Type 2 diabetes

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE ACTIVATOR; MITOCHONDRIAL DNA; ORPHAN NUCLEAR RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1BETA; RECEPTOR INTERACTING PROTEIN 140; RESVERATROL; TRANSCRIPTION FACTOR; ANTIDIABETIC AGENT;

AEROBIC METABOLISM; ARTICLE; BIOGENESIS; BROWN ADIPOCYTE; CALORIC RESTRICTION; CHRONIC INFLAMMATION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DRUG TARGETING; ENDOPLASMIC RETICULUM STRESS; EXERCISE; FATTY ACID BLOOD LEVEL; GENE EXPRESSION; GENETIC ASSOCIATION; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; GLUCOSE OXIDATION; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIFESTYLE MODIFICATION; LIPID STORAGE; LIPOTOXICITY; LIVER; MACROPHAGE; MITOCHONDRIAL DYNAMICS; MITOCHONDRIAL GENE; MITOCHONDRIAL RESPIRATION; MITOCHONDRION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REGULATORY MECHANISM; SKELETAL MUSCLE; TRANSCRIPTION REGULATION; WHITE ADIPOSE TISSUE; ANIMAL; DRUG DELIVERY SYSTEM; DRUG EFFECTS; ENERGY METABOLISM; METABOLISM; PHYSIOLOGY; PROCEDURES; TREATMENT OUTCOME;

ANIMALS; DRUG DELIVERY SYSTEMS; ENERGY METABOLISM; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN RESISTANCE; MITOCHONDRIA; TREATMENT OUTCOME;

EID: 84911427884     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/1381612820666140306102514     Document Type: Article

References (367)

1. [1] Danaei G, Finucane MM, Lu Y, et al. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2011; 378(9785): 31-40
2. [2] Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2009; 87(1): 4-14
3. [3] Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979; 241(19): 2035-8
4. [4] Fong DS, Aiello L, Gardner TW, et al. Retinopathy in diabetes. Diabetes Care 2004; 27 (Suppl 1): S84-7
5. [5] Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol 2012; 11(6): 521-34
6. [6] Alsaad KO, Herzenberg AM. Distinguishing diabetic nephropathy from other causes of glomerulosclerosis: an update. J Clin Pathol 2007; 60(1): 18-26
7. [7] Reaven GM, Hollenbeck C, Jeng CY, Wu MS, Chen YD. Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes 1988; 37(8): 1020-4
8. [8] Haffner SM, Stern MP, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia in a population at high risk for non-insulindependent diabetes mellitus. N Engl J Med 1986; 315(4): 220-4
9. [9] Lillioja S, Mott DM, Howard BV, et al. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 1988; 318(19): 1217-25
10. [10] Eriksson J, Franssila-Kallunki A, Ekstrand A, et al. Early metabolic defects in persons at increased risk for non-insulindependent diabetes mellitus. N Engl J Med 1989; 321(6): 337-43
11. [11] Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Increased insulin concentrations in nondiabetic offspring of diabetic parents. N Engl J Med 1988; 319(20): 1297-301
12. [12] Perseghin G, Ghosh S, Gerow K, Shulman GI. Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes 1997; 46(6): 1001-9
13. [13] Vauhkonen I, Niskanen L, Vanninen E, et al. Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands. J Clin Invest 1998; 101(1): 86-96
14. [14] Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 1990; 113(12): 909-15
15. [15] Goldfine AB, Bouche C, Parker RA, et al. Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease. Proc Natl Acad Sci USA 2003; 100(5): 2724-9
16. [16] Martin BC, Warram JH, Krolewski AS, et al. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet 1992; 340(8825): 925-9
17. [17] Tattersal RB, Fajans SS. Prevalence of diabetes and glucose intolerance in 199 offspring of thirty-seven conjugal diabetic parents. Diabetes 1975; 24(5): 452-62
18. Billings LK, Florez JC. The genetics of type 2 diabetes: what have we learned from GWAS? Ann N Y Acad Sci 2010; 1212(59-77).
19. [19] Herder C, Roden M. Genetics of type 2 diabetes: pathophysiologic and clinical relevance. Eur J Clin Invest 2011; 41(6): 679-92
20. [20] Watanabe RM. The genetics of insulin resistance: Where's Waldo? Curr Diab Rep 2010; 10(6): 476-84
21. [21] Riccardi G, Rivellese AA. Dietary treatment of the metabolic syndrome--the optimal diet. Br J Nutr 2000; 83 (Suppl 1): S143-8
22. [22] Hamilton MT, Hamilton DG, Zderic TW. Role of low energy expenditure and sitting in obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Diabetes 2007; 56(11): 2655-67
23. [23] Manson JE, Rimm EB, Stampfer MJ, et al. Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet 1991; 338(8770): 774-8
24. [24] Despres JP. Abdominal obesity as important component of insulinresistance syndrome. Nutrition 1993; 9(5): 452-9
25. [25] Rich-Edwards JW, Colditz GA, Stampfer MJ, et al. Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med 1999; 130(4 Pt 1): 278-84
26. [26] Lonnroth P, Smith U. Aging enhances the insulin resistance in obesity through both receptor and postreceptor alterations. J Clin Endocrinol Metab 1986; 62(2): 433-7
27. [27] Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963; 1(7285): 785-9
28. [28] Santomauro AT, Boden G, Silva ME, et al. Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes 1999; 48(9): 1836-41
29. [29] Oakes ND, Cooney GJ, Camilleri S, Chisholm DJ, Kraegen EW. Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes 1997; 46(11): 1768-74
30. [30] Bachmann OP, Dahl DB, Brechtel K, et al. Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans. Diabetes 2001; 50(11): 2579-84
31. [31] Pan DA, Lillioja S, Kriketos AD, et al. Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 1997; 46(6): 983-8
32. [32] Hubinger A, Knode O, Susanto F, Reinauer H, Gries FA. Effects of the carnitine-acyltransferase inhibitor etomoxir on insulin sensitivity, energy expenditure and substrate oxidation in NIDDM. Horm Metab Res 1997; 29(9): 436-9
33. [33] Hubinger A, Weikert G, Wolf HP, Gries FA. The effect of etomoxir on insulin sensitivity in type 2 diabetic patients. Horm Metab Res 1992; 24(3): 115-8
34. [34] Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999; 103(2): 253-9
35. [35] Roden M, Price TB, Perseghin G, et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996; 97(12): 2859-65
36. [36] Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012; 148(5): 852-71
37. [37] Krssak M, Falk Petersen K, Dresner A, et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 1999; 42(1): 113-6
38. [38] Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002; 51(7): 2005-11
39. [39] Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002; 277(52): 50230-6
40. [40] Amati F, Dube JJ, Alvarez-Carnero E, et al. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes 2011; 60(10): 2588-97
41. [41] Griffin ME, Marcucci MJ, Cline GW, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999; 48(6): 1270-4
42. [42] Powell DJ, Hajduch E, Kular G, Hundal HS. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol Cell Biol 2003; 23(21): 7794-808
43. [43] Timmers S, Nabben M, Bosma M, et al. Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity. Proc Natl Acad Sci USA 2012; 109(29): 11711-6
44. [44] Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005; 115(5): 1111-9
45. [45] Clowes GH, Jr., Martin H, Walji S, et al. Blood insulin responses to blood glucose levels in high output sepsis and spetic shock. Am J Surg 1978; 135(4): 577-83
46. [46] Iochida LC, Tominaga M, Matsumoto M, Sekikawa A, Sasaki H. Insulin resistance in septic rats--a study by the euglycemic clamp technique. Life Sci 1989; 45(17): 1567-73
47. [47] Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995; 95(5): 2409-15
48. [48] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259(5091): 87-91
49. [49] Nguyen MT, Favelyukis S, Nguyen AK, et al. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNKdependent pathways. J Biol Chem 2007; 282(48): 35279-92
50. [50] Zick Y. Role of Ser/Thr kinases in the uncoupling of insulin signaling. Int J Obes Relat Metab Disord 2003; 27 (Suppl 3): S56-60
51. [51] Shi H, Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006; 116(11): 3015-25
52. [52] Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010; 140(6): 900-17
53. [53] Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306(5695): 457-61
54. [54] Gregor MF, Yang L, Fabbrini E, et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 2009; 58(3): 693-700
55. [55] Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006; 313(5790): 1137-40
56. [56] Deng J, Lu PD, Zhang Y, et al. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 2004; 24(23): 10161-8
57. [57] Urano F, Wang X, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000; 287(5453): 664-6
58. [58] Cunha DA, Hekerman P, Ladriere L, et al. Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J Cell Sci 2008; 121(Pt 14): 2308-18
59. [59] Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006; 147(2): 943-51
60. [60] Leloup C, Tourrel-Cuzin C, Magnan C, et al. Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes 2009; 58(3): 673-81
61. [61] Maechler P, Wollheim CB. Mitochondrial signals in glucosestimulated insulin secretion in the beta cell. J Physiol 2000; 529 (Pt 1): 49-56
62. Newgard CB, McGarry JD. Metabolic coupling factors in pancreatic beta-cell signal transduction. Annu Rev Biochem 1995; 64(689-719).
63. [63] Maassen JA, t Hart LM, Janssen GM, et al. Mitochondrial diabetes and its lessons for common Type 2 diabetes. Biochem Soc Trans 2006; 34(Pt 5): 819-23
64. [64] Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005; 307(5708): 384-7
65. [65] Goldstein BJ, Mahadev K, Wu X, Zhu L, Motoshima H. Role of insulin-induced reactive oxygen species in the insulin signaling pathway. Antioxid Redox Signal 2005; 7(7-8): 1021-31
66. [66] Pomytkin IA. H2O2 Signalling Pathway: A Possible Bridge between Insulin Receptor and Mitochondria. Curr Neuropharmacol 2012; 10(4): 311-20
67. [67] Mahadev K, Wu X, Zilbering A, et al. Hydrogen peroxide generated during cellular insulin stimulation is integral to activation of the distal insulin signaling cascade in 3T3-L1 adipocytes. J Biol Chem 2001; 276(52): 48662-9
68. Storozhevykh TP, Senilova YE, Persiyantseva NA, Pinelis VG, Pomytkin IA. Mitochondrial respiratory chain is involved in insulin-stimulated hydrogen peroxide production and plays an integral role in insulin receptor autophosphorylation in neurons. BMC Neurosci 2007; 8(84).
69. [69] Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 2012; 13(9): 566-78
70. [70] Pagliarini DJ, Calvo SE, Chang B, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 2008; 134(1): 112-23
71. [71] Mootha VK, Bunkenborg J, Olsen JV, et al. Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell 2003; 115(5): 629-40
72. Hock MB, Kralli A. Transcriptional control of mitochondrial biogenesis and function. Annu Rev Physiol 2009; 71(177-203).
73. Falkenberg M, Larsson NG, Gustafsson CM. DNA replication and transcription in mammalian mitochondria. Annu Rev Biochem 2007; 76(679-99).
74. [74] Larsson NG, Wang J, Wilhelmsson H, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet 1998; 18(3): 231-6
75. [75] Medeiros DM. Assessing mitochondria biogenesis. Methods 2008; 46(4): 288-94
76. [76] Metodiev MD, Lesko N, Park CB, et al. Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome. Cell Metab 2009; 9(4): 386-97
77. [77] Evans MJ, Scarpulla RC. Interaction of nuclear factors with multiple sites in the somatic cytochrome c promoter. Characterization of upstream NRF-1, ATF, and intron Sp1 recognition sequences. J Biol Chem 1989; 264(24): 14361-8
78. [78] Virbasius JV, Scarpulla RC. Transcriptional activation through ETS domain binding sites in the cytochrome c oxidase subunit IV gene. Mol Cell Biol 1991; 11(11): 5631-8
79. [79] Kelly DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 2004; 18(4): 357-68
80. [80] Sakamaki T, Casimiro MC, Ju X, et al. Cyclin D1 determines mitochondrial function in vivo. Mol Cell Biol 2006; 26(14): 5449-69
81. [81] Huo L, Scarpulla RC. Mitochondrial DNA instability and periimplantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice. Mol Cell Biol 2001; 21(2): 644-54
82. [82] LaMarco K, Thompson CC, Byers BP, Walton EM, McKnight SL. Identification of Ets-and notch-related subunits in GA binding protein. Science 1991; 253(5021): 789-92
83. [83] Scarpulla RC. Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim Biophys Acta 2002; 1576(1-2): 1-14
84. Villena JA, Vinas O, Mampel T, et al. Regulation of mitochondrial biogenesis in brown adipose tissue: nuclear respiratory factor-2/GA-binding protein is responsible for the transcriptional regulation of the gene for the mitochondrial ATP synthase beta subunit. Biochem J 1998; 331 (Pt 1)(121-7).
85. [85] Ristevski S, O'Leary DA, Thornell AP, et al. The ETS transcription factor GABPalpha is essential for early embryogenesis. Mol Cell Biol 2004; 24(13): 5844-9
86. [86] O'Leary DA, Noakes PG, Lavidis NA, et al. Targeting of the ETS factor GABPalpha disrupts neuromuscular junction synaptic function. Mol Cell Biol 2007; 27(9): 3470-80
87. [87] Lee CH, Olson P, Evans RM. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 2003; 144(6): 2201-7
88. [88] Lee SS, Pineau T, Drago J, et al. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 1995; 15(6): 3012-22
89. [89] Burkart EM, Sambandam N, Han X, et al. Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart. J Clin Invest 2007; 117(12): 3930-9
90. [90] Wang YX, Lee CH, Tiep S, et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 2003; 113(2): 159-70
91. [91] Wang YX, Zhang CL, Yu RT, et al. Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol 2004; 2(10): e294
92. [92] Eichner LJ, Giguere V. Estrogen related receptors (ERRs): a new dawn in transcriptional control of mitochondrial gene networks. Mitochondrion 2011; 11(4): 544-52
93. [93] Schreiber SN, Emter R, Hock MB, et al. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc Natl Acad Sci USA 2004; 101(17): 6472-7
94. [94] Villena JA, Kralli A. ERRalpha: a metabolic function for the oldest orphan. Trends Endocrinol Metab 2008; 19(8): 269-76
95. [95] Villena JA, Hock MB, Chang WY, et al. Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis. Proc Natl Acad Sci USA 2007; 104(4): 1418-23
96. [96] Huss JM, Imahashi K, Dufour CR, et al. The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload. Cell Metab 2007; 6(1): 25-37
97. [97] Dufour CR, Wilson BJ, Huss JM, et al. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma. Cell Metab 2007; 5(5): 345-56
98. [98] Alaynick WA, Kondo RP, Xie W, et al. ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart. Cell Metab 2007; 6(1): 13-24
99. [99] Puigserver P, Wu Z, Park CW, et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998; 92(6): 829-39
100. [100] Yoon JC, Puigserver P, Chen G, et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 2001; 413(6852): 131-8
101. [101] Handschin C, Kobayashi YM, Chin S, et al. PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev 2007; 21(7): 770-83
102. [102] Lin J, Wu H, Tarr PT, et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 2002; 418(6899): 797-801
103. [103] Lin J, Wu PH, Tarr PT, et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 2004; 119(1): 121-35
104. [104] Scarpulla RC, Vega RB, Kelly DP. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol Metab 2012; 23(9): 459-66
105. [105] Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 2011; 93(4): 884S-90
106. [106] Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 2005; 1(6): 361-70
107. [107] Leone TC, Lehman JJ, Finck BN, et al. PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 2005; 3(4): e101
108. [108] Arany Z, Novikov M, Chin S, et al. Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha. Proc Natl Acad Sci USA 2006; 103(26): 10086-91
109. [109] Lai L, Leone TC, Zechner C, et al. Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev 2008; 22(14): 1948-61
110. [110] Uldry M, Yang W, St-Pierre J, et al. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab 2006; 3(5): 333-41
111. [111] St-Pierre J, Lin J, Krauss S, et al. Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells. J Biol Chem 2003; 278(29): 26597-603
112. [112] Lelliott CJ, Medina-Gomez G, Petrovic N, et al. Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol 2006; 4(11): e369
113. [113] Sonoda J, Mehl IR, Chong LW, Nofsinger RR, Evans RM. PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc Natl Acad Sci USA 2007; 104(12): 5223-8
114. [114] Vianna CR, Huntgeburth M, Coppari R, et al. Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance. Cell Metab 2006; 4(6): 453-64
115. [115] Enguix N, Pardo R, González A, et al. Mice lacking PGC-1beta in adipose tissues reveal a dissociation between mitochondrial dysfunction and insulin resistance. Molecular Metabolism 2013; DOI: 10.1016/j.molmet.2013.05.004
116. [116] Pardo R, Enguix N, Lasheras J, et al. Rosiglitazone-induced mitochondrial biogenesis in white adipose tissue is independent of peroxisome proliferator-activated receptor gamma coactivator-1alpha. PLoS One 2011; 6(11): e26989
117. [117] Scarpulla RC. Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator. Ann N Y Acad Sci 2008; 1147: 321-34
118. [118] He X, Sun C, Wang F, et al. Peri-implantation lethality in mice lacking the PGC-1-related coactivator protein. Dev Dyn 2012; 241(5): 975-83
119. [119] Powelka AM, Seth A, Virbasius JV, et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J Clin Invest 2006; 116(1): 125-36
120. [120] Seth A, Steel JH, Nichol D, et al. The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab 2007; 6(3): 236-45
121. [121] Lillioja S, Young AA, Culter CL, et al. Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest 1987; 80(2): 415-24
122. [122] Simoneau JA, Colberg SR, Thaete FL, Kelley DE. Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women. FASEB J 1995; 9(2): 273-8
123. [123] James DE, Jenkins AB, Kraegen EW. Heterogeneity of insulin action in individual muscles in vivo: euglycemic clamp studies in rats. Am J Physiol 1985; 248(5 Pt 1): E567-74
124. [124] Simoneau JA, Kelley DE. Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM. J Appl Physiol 1997; 83(1): 166-71
125. [125] Vondra K, Rath R, Bass A, et al. Enzyme activities in quadriceps femoris muscle of obese diabetic male patients. Diabetologia 1977; 13(5): 527-9
126. [126] Mensink M, Blaak EE, van Baak MA, Wagenmakers AJ, Saris WH. Plasma free Fatty Acid uptake and oxidation are already diminished in subjects at high risk for developing type 2 diabetes. Diabetes 2001; 50(11): 2548-54
127. [127] Blaak EE, van Aggel-Leijssen DP, Wagenmakers AJ, Saris WH, van Baak MA. Impaired oxidation of plasma-derived fatty acids in type 2 diabetic subjects during moderate-intensity exercise. Diabetes 2000; 49(12): 2102-7
128. [128] Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002; 51(10): 2944-50
129. [129] Ritov VB, Menshikova EV, He J, et al. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 2005; 54(1): 8-14
130. [130] Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003; 300(5622): 1140-2
131. [131] Befroy DE, Petersen KF, Dufour S, et al. Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 2007; 56(5): 1376-81
132. [132] Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004; 350(7): 664-71
133. [133] Petersen KF, Dufour S, Shulman GI. Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulinresistant offspring of type 2 diabetic parents. PLoS Med 2005; 2(9): e233
134. [134] Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, et al. Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia 2007; 50(1): 113-20
135. [135] Johannsen DL, Conley KE, Bajpeyi S, et al. Ectopic lipid accumulation and reduced glucose tolerance in elderly adults are accompanied by altered skeletal muscle mitochondrial activity. J Clin Endocrinol Metab 2012; 97(1): 242-50
136. [136] Wilson-Fritch L, Burkart A, Bell G, et al. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol Cell Biol 2003; 23(3): 1085-94
137. [137] Tormos KV, Anso E, Hamanaka RB, et al. Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab 2011; 14(4): 537-44
138. [138] Bjerve KS, Daae LN, Bremer J. Phosphatidic acid biosynthesis in rat liver mitochondria and microsomal fractions. Regulation of fatty acid positional specificity. Biochem J 1976; 158(2): 249-54
139. [139] Kaaman M, Sparks LM, van Harmelen V, et al. Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue. Diabetologia 2007; 50(12): 2526-33
140. [140] Koh EH, Park JY, Park HS, et al. Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes 2007; 56(12): 2973-81
141. [141] Kusminski CM, Holland WL, Sun K, et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med 2012; 18(10): 1539-49
142. [142] Bryson JM, Cooney GJ, Wensley VR, Phuyal JL, Caterson ID. Tissue differences in the response of the pyruvate dehydrogenase complex to a glucose load during the development of obesity in gold-thioglucose-obese mice. Biochem J 1995; 305 (Pt 3): 811-6
143. [143] Choo HJ, Kim JH, Kwon OB, et al. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 2006; 49(4): 784-91
144. [144] Rong JX, Qiu Y, Hansen MK, et al. Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone. Diabetes 2007; 56(7): 1751-60
145. [145] Chattopadhyay M, Guhathakurta I, Behera P, et al. Mitochondrial bioenergetics is not impaired in nonobese subjects with type 2 diabetes mellitus. Metabolism 2011; 60(12): 1702-10
146. [146] Kraunsoe R, Boushel R, Hansen CN, et al. Mitochondrial respiration in subcutaneous and visceral adipose tissue from patients with morbid obesity. J Physiol 2010; 588(Pt 12): 2023-32
147. [147] Giorgino F, Laviola L, Eriksson JW. Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies. Acta Physiol Scand 2005; 183(1): 13-30
148. [148] Rector RS, Thyfault JP, Uptergrove GM, et al. Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J Hepatol 2010; 52(5): 727-36
149. [149] Raffaella C, Francesca B, Italia F, et al. Alterations in hepatic mitochondrial compartment in a model of obesity and insulin resistance. Obesity (Silver Spring) 2008; 16(5): 958-64
150. [150] Mantena SK, Vaughn DP, Andringa KK, et al. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. Biochem J 2009; 417(1): 183-93
151. [151] Poussin C, Ibberson M, Hall D, et al. Oxidative phosphorylation flexibility in the liver of mice resistant to high-fat diet-induced hepatic steatosis. Diabetes 2011; 60(9): 2216-24
152. [152] Zhang D, Liu ZX, Choi CS, et al. Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci USA 2007; 104(43): 17075-80
153. [153] Szendroedi J, Schmid AI, Chmelik M, et al. Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes. PLoS Med 2007; 4(5): e154
154. [154] Cortez-Pinto H, Chatham J, Chacko VP, et al. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 1999; 282(17): 1659-64
155. [155] Perez-Carreras M, Del Hoyo P, Martin MA, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 2003; 38(4): 999-1007
156. [156] Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006; 43(2 Suppl 1): S99-S112
157. [157] Boushel R, Gnaiger E, Schjerling P, et al. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 2007; 50(4): 790-6
158. [158] Morino K, Petersen KF, Dufour S, et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 2005; 115(12): 3587-93
159. [159] Ukropcova B, Sereda O, de Jonge L, et al. Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle. Diabetes 2007; 56(3): 720-7
160. [160] Patti ME, Butte AJ, Crunkhorn S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 2003; 100(14): 8466-71
161. [161] Mootha VK, Lindgren CM, Eriksson KF, et al. PGC-1alpharesponsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34(3): 267-73
162. [162] Bogacka I, Xie H, Bray GA, Smith SR. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 2005; 54(5): 1392-9
163. [163] Dahlman I, Forsgren M, Sjogren A, et al. Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor-alpha. Diabetes 2006; 55(6): 1792-9
164. [164] Krishnan J, Danzer C, Simka T, et al. Dietary obesity-associated Hif1alpha activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. Genes Dev 2012; 26(3): 259-70
165. [165] Mustelin L, Pietilainen KH, Rissanen A, et al. Acquired obesity and poor physical fitness impair expression of genes of mitochondrial oxidative phosphorylation in monozygotic twins discordant for obesity. Am J Physiol Endocrinol Metab 2008; 295(1): E148-54
166. [166] Sutherland LN, Capozzi LC, Turchinsky NJ, Bell RC, Wright DC. Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance. Am J Physiol Endocrinol Metab 2008; 295(5): E1076-83
167. [167] Wilson-Fritch L, Nicoloro S, Chouinard M, et al. Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest 2004; 114(9): 1281-9
168. [168] Pratley RE, Thompson DB, Prochazka M, et al. An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest 1998; 101(8): 1757-64
169. [169] Ek J, Andersen G, Urhammer SA, et al. Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus. Diabetologia 2001; 44(12): 2220-6
170. [170] Hara K, Tobe K, Okada T, et al. A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes. Diabetologia 2002; 45(5): 740-3
171. [171] Barres R, Osler ME, Yan J, et al. Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab 2009; 10(3): 189-98
172. [172] Bach D, Pich S, Soriano FX, et al. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. J Biol Chem 2003; 278(19): 17190-7
173. [173] Bach D, Naon D, Pich S, et al. Expression of Mfn2, the Charcot-Marie-Tooth neuropathy type 2A gene, in human skeletal muscle: effects of type 2 diabetes, obesity, weight loss, and the regulatory role of tumor necrosis factor alpha and interleukin-6. Diabetes 2005; 54(9): 2685-93
174. [174] Sebastian D, Hernandez-Alvarez MI, Segales J, et al. Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci USA 2012; 109(14): 5523-8
175. [175] Wredenberg A, Freyer C, Sandstrom ME, et al. Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance. Biochem Biophys Res Commun 2006; 350(1): 202-7
176. [176] Vernochet C, Mourier A, Bezy O, et al. Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab 2012; 16(6): 765-76
177. [177] Pospisilik JA, Knauf C, Joza N, et al. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 2007; 131(3): 476-91
178. [178] Handschin C, Choi CS, Chin S, et al. Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. J Clin Invest 2007; 117(11): 3463-74
179. [179] Bonnard C, Durand A, Peyrol S, et al. Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 2008; 118(2): 789-800
180. [180] Hancock CR, Han DH, Chen M, et al. High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci USA 2008; 105(22): 7815-20
181. [181] Garcia-Roves P, Huss JM, Han DH, et al. Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle. Proc Natl Acad Sci USA 2007; 104(25): 10709-13
182. [182] Holloway GP, Gurd BJ, Snook LA, Lally J, Bonen A. Compensatory increases in nuclear PGC1alpha protein are primarily associated with subsarcolemmal mitochondrial adaptations in ZDF rats. Diabetes 2010; 59(4): 819-28
183. [183] McAinch AJ, Lee JS, Bruce CR, et al. Dietary regulation of fat oxidative gene expression in different skeletal muscle fiber types. Obes Res 2003; 11(12): 1471-9
184. [184] Turner N, Bruce CR, Beale SM, et al. Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipidinduced insulin resistance in rodents. Diabetes 2007; 56(8): 2085-92
185. [185] Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab 2011; 14(6): 804-10
186. [186] Holloszy JO. Skeletal muscle "mitochondrial deficiency" does not mediate insulin resistance. Am J Clin Nutr 2009; 89(1): 463S-6S
187. [187] Cheng Z, Guo S, Copps K, et al. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med 2009; 15(11): 1307-11
188. [188] Belke DD, Betuing S, Tuttle MJ, et al. Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin Invest 2002; 109(5): 629-39
189. [189] Boudina S, Bugger H, Sena S, et al. Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 2009; 119(9): 1272-83
190. [190] Laustsen PG, Russell SJ, Cui L, et al. Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function. Mol Cell Biol 2007; 27(5): 1649-64
191. [191] Liu S, Okada T, Assmann A, et al. Insulin signaling regulates mitochondrial function in pancreatic beta-cells. PLoS One 2009; 4(11): e7983
192. [192] Sreekumar R, Halvatsiotis P, Schimke JC, Nair KS. Gene expression profile in skeletal muscle of type 2 diabetes and the effect of insulin treatment. Diabetes 2002; 51(6): 1913-20
193. [193] Asmann YW, Stump CS, Short KR, et al. Skeletal muscle mitochondrial functions, mitochondrial DNA copy numbers, and gene transcript profiles in type 2 diabetic and nondiabetic subjects at equal levels of low or high insulin and euglycemia. Diabetes 2006; 55(12): 3309-19
194. [194] Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical activity/exercise and type 2 diabetes. Diabetes Care 2004; 27(10): 2518-39
195. [195] Zierath JR. Invited review: Exercise training-induced changes in insulin signaling in skeletal muscle. J Appl Physiol 2002; 93(2): 773-81
196. [196] Snowling NJ, Hopkins WG. Effects of different modes of exercise training on glucose control and risk factors for complications in type 2 diabetic patients: a meta-analysis. Diabetes Care 2006; 29(11): 2518-27
197. Willcox BJ, Willcox DC, Todoriki H, et al. Caloric restriction, the traditional Okinawan diet, and healthy aging: the diet of the world's longest-lived people and its potential impact on morbidity and life span. Ann N Y Acad Sci 2007; 1114(434-55).
198. [198] Mattison JA, Roth GS, Beasley TM, et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 2012; 489(7415): 318-21
199. [199] Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009; 325(5937): 201-4
200. [200] Redman LM, Ravussin E. Caloric restriction in humans: impact on physiological, psychological, and behavioral outcomes. Antioxid Redox Signal 2011; 14(2): 275-87
201. [201] Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994; 79(7): 1147-56
202. [202] Moitra J, Mason MM, Olive M, et al. Life without white fat: a transgenic mouse. Genes Dev 1998; 12(20): 3168-81
203. [203] Chao L, Marcus-Samuels B, Mason MM, et al. Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. J Clin Invest 2000; 106(10): 1221-8
204. [204] Boden G, Homko C, Mozzoli M, et al. Thiazolidinediones upregulate fatty acid uptake and oxidation in adipose tissue of diabetic patients. Diabetes 2005; 54(3): 880-5
205. [205] Sears DD, Hsiao G, Hsiao A, et al. Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization. Proc Natl Acad Sci USA 2009; 106(44): 18745-50
206. [206] Laplante M, Festuccia WT, Soucy G, et al. Mechanisms of the depot specificity of peroxisome proliferator-activated receptor gamma action on adipose tissue metabolism. Diabetes 2006; 55(10): 2771-8
207. [207] Tiraby C, Tavernier G, Lefort C, et al. Acquirement of brown fat cell features by human white adipocytes. J Biol Chem 2003; 278(35): 33370-6
208. [208] Hondares E, Mora O, Yubero P, et al. Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptorcoactivator (PGC)-1alpha gene transcription: an autoregulatory loop controls PGC-1alpha expression in adipocytes via peroxisome proliferator-activated receptor-gamma coactivation. Endocrinology 2006; 147(6): 2829-38
209. [209] Kleiner S, Mepani RJ, Laznik D, et al. Development of insulin resistance in mice lacking PGC-1alpha in adipose tissues. Proc Natl Acad Sci USA 2012; 109(24): 9635-40
210. [210] Lodhi IJ, Semenkovich CF. Why we should put clothes on mice. Cell Metab 2009; 9(2): 111-2
211. [211] Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab 2012; 15(3): 395-404
212. [212] Deng T, Sieglaff DH, Zhang A, et al. A peroxisome proliferatoractivated receptor gamma (PPARgamma)/PPARgamma coactivator 1beta autoregulatory loop in adipocyte mitochondrial function. J Biol Chem 2011; 286(35): 30723-31
213. [213] Lapsys NM, Kriketos AD, Lim-Fraser M, et al. Expression of genes involved in lipid metabolism correlate with peroxisome proliferator-activated receptor gamma expression in human skeletal muscle. J Clin Endocrinol Metab 2000; 85(11): 4293-7
214. [214] Mensink M, Hesselink MK, Russell AP, et al. Improved skeletal muscle oxidative enzyme activity and restoration of PGC-1 alpha and PPAR beta/delta gene expression upon rosiglitazone treatment in obese patients with type 2 diabetes mellitus. Int J Obes (Lond) 2007; 31(8): 1302-10
215. [215] Skov V, Glintborg D, Knudsen S, et al. Pioglitazone enhances mitochondrial biogenesis and ribosomal protein biosynthesis in skeletal muscle in polycystic ovary syndrome. PLoS One 2008; 3(6): e2466
216. [216] Cha BS, Ciaraldi TP, Park KS, et al. Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPARgamma agonists. Am J Physiol Endocrinol Metab 2005; 289(1): E151-9
217. [217] Pagel-Langenickel I, Bao J, Joseph JJ, et al. PGC-1alpha integrates insulin signaling, mitochondrial regulation, and bioenergetic function in skeletal muscle. J Biol Chem 2008; 283(33): 22464-72
218. [218] Wilmsen HM, Ciaraldi TP, Carter L, et al. Thiazolidinediones upregulate impaired fatty acid uptake in skeletal muscle of type 2 diabetic subjects. Am J Physiol Endocrinol Metab 2003; 285(2): E354-62
219. [219] Pagel-Langenickel I, Schwartz DR, Arena RA, et al. A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in Type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol 2007; 293(5): H2659-66
220. [220] Schrauwen-Hinderling VB, Mensink M, Hesselink MK, et al. The insulin-sensitizing effect of rosiglitazone in type 2 diabetes mellitus patients does not require improved in vivo muscle mitochondrial function. J Clin Endocrinol Metab 2008; 93(7): 2917-21
221. [221] Norris AW, Chen L, Fisher SJ, et al. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Invest 2003; 112(4): 608-18
222. [222] Ogawa S, Lozach J, Benner C, et al. Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 2005; 122(5): 707-21
223. [223] Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998; 391(6662): 79-82
224. [224] Welch JS, Ricote M, Akiyama TE, Gonzalez FJ, Glass CK. PPARgamma and PPARdelta negatively regulate specific subsets of lipopolysaccharide and IFN-gamma target genes in macrophages. Proc Natl Acad Sci USA 2003; 100(11): 6712-7
225. [225] Hevener AL, Olefsky JM, Reichart D, et al. Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 2007; 117(6): 1658-69
226. [226] Vats D, Mukundan L, Odegaard JI, et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 2006; 4(1): 13-24
227. [227] Feinstein DL, Spagnolo A, Akar C, et al. Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key? Biochem Pharmacol 2005; 70(2): 177-88
228. [228] Brunmair B, Staniek K, Gras F, et al. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 2004; 53(4): 1052-9
229. [229] Gelman L, Feige JN, Desvergne B. Molecular basis of selective PPARgamma modulation for the treatment of Type 2 diabetes. Biochim Biophys Acta 2007; 1771(8): 1094-107
230. Zhang F, Lavan BE, Gregoire FM. Selective Modulators of PPARgamma Activity: Molecular Aspects Related to Obesity and Side-Effects. PPAR Res 2007; 2007(32696).
231. [231] Burgermeister E, Schnoebelen A, Flament A, et al. A novel partial agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma) recruits PPARgamma-coactivator-1alpha, prevents triglyceride accumulation, and potentiates insulin signaling in vitro. Mol Endocrinol 2006; 20(4): 809-30
232. [232] Schupp M, Clemenz M, Gineste R, et al. Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. Diabetes 2005; 54(12): 3442-52
233. [233] Misra P, Chakrabarti R, Vikramadithyan RK, et al. PAT5A: a partial agonist of peroxisome proliferator-activated receptor gamma is a potent antidiabetic thiazolidinedione yet weakly adipogenic. J Pharmacol Exp Ther 2003; 306(2): 763-71
234. [234] Sinclair DA. Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev 2005; 126(9): 987-1002
235. [235] Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science 2010; 328(5976): 321-6
236. [236] Chen D, Bruno J, Easlon E, et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev 2008; 22(13): 1753-7
237. [237] Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004; 305(5682): 390-2
238. [238] Nisoli E, Tonello C, Cardile A, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 2005; 310(5746): 314-7
239. [239] Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005; 434(7029): 113-8
240. [240] Banks AS, Kon N, Knight C, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab 2008; 8(4): 333-41
241. [241] Bordone L, Cohen D, Robinson A, et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 2007; 6(6): 759-67
242. [242] Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschop MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci USA 2008; 105(28): 9793-8
243. [243] Li Y, Xu S, Giles A, et al. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J 2011; 25(5): 1664-79
244. Herranz D, Munoz-Martin M, Canamero M, et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 2010; 1(3).
245. [245] Firestein R, Blander G, Michan S, et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One 2008; 3(4): e2020
246. [246] Burnett C, Valentini S, Cabreiro F, et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 2011; 477(7365): 482-5
247. [247] Kaeberlein M, Kirkland KT, Fields S, Kennedy BK. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol 2004; 2(9): E296
248. [248] Bordone L, Motta MC, Picard F, et al. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 2006; 4(2): e31
249. [249] McBurney MW, Yang X, Jardine K, et al. The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol 2003; 23(1): 38-54
250. [250] Xu F, Gao Z, Zhang J, et al. Lack of SIRT1 (Mammalian Sirtuin 1) activity leads to liver steatosis in the SIRT1+/-mice: a role of lipid mobilization and inflammation. Endocrinology 2010; 151(6): 2504-14
251. [251] Frescas D, Valenti L, Accili D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 2005; 280(21): 20589-95
252. [252] Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem 2005; 280(16): 16456-60
253. [253] Ponugoti B, Kim DH, Xiao Z, et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem 2010; 285(44): 33959-70
254. [254] Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004; 429(6993): 771-6
255. [255] Lin SJ, Kaeberlein M, Andalis AA, et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 2002; 418(6895): 344-8
256. [256] Masoro EJ, Yu BP, Bertrand HA. Action of food restriction in delaying the aging process. Proc Natl Acad Sci USA 1982; 79(13): 4239-41
257. [257] Civitarese AE, Carling S, Heilbronn LK, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007; 4(3): e76
258. [258] Park SK, Prolla TA. Gene expression profiling studies of aging in cardiac and skeletal muscles. Cardiovasc Res 2005; 66(2): 205-12
259. [259] Gerhart-Hines Z, Rodgers JT, Bare O, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 2007; 26(7): 1913-23
260. [260] Finley LW, Lee J, Souza A, et al. Skeletal muscle transcriptional coactivator PGC-1alpha mediates mitochondrial, but not metabolic, changes during calorie restriction. Proc Natl Acad Sci USA 2012; 109(8): 2931-6
261. [261] Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425(6954): 191-6
262. [262] Chung JH, Manganiello V, Dyck JR. Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 2012; 22(10): 546-54
263. [263] Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444(7117): 337-42
264. [264] Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006; 127(6): 1109-22
265. [265] Barger JL, Kayo T, Vann JM, et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 2008; 3(6): e2264
266. [266] Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays agerelated deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008; 8(2): 157-68
267. [267] Brasnyo P, Molnar GA, Mohas M, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr 2011; 106(3): 383-9
268. [268] Marchal J, Blanc S, Epelbaum J, Aujard F, Pifferi F. Effects of chronic calorie restriction or dietary resveratrol supplementation on insulin sensitivity markers in a primate, Microcebus murinus. PLoS One 2012; 7(3): e34289
269. [269] Timmers S, Konings E, Bilet L, 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(5): 612-22
270. [270] Beher D, Wu J, Cumine S, et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des 2009; 74(6): 619-24
271. [271] Kaeberlein M, McDonagh T, Heltweg B, et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 2005; 280(17): 17038-45
272. [272] Milne JC, Lambert PD, Schenk S, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007; 450(7170): 712-6
273. [273] Feige JN, Lagouge M, Canto C, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab 2008; 8(5): 347-58
274. Smith JJ, Kenney RD, Gagne DJ, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol 2009; 3(31).
275. [275] Hawkins M, Tonelli J, Kishore P, et al. Contribution of elevated free fatty acid levels to the lack of glucose effectiveness in type 2 diabetes. Diabetes 2003; 52(11): 2748-58
276. [276] Canto C, Houtkooper RH, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 2012; 15(6): 838-47
277. [277] Oakhill JS, Steel R, Chen ZP, et al. AMPK is a direct adenylate charge-regulated protein kinase. Science 2011; 332(6036): 1433-5
278. [278] Xiao B, Sanders MJ, Underwood E, et al. Structure of mammalian AMPK and its regulation by ADP. Nature 2011; 472(7342): 230-3
279. [279] Suter M, Riek U, Tuerk R, et al. Dissecting the role of 5'-AMP for allosteric stimulation, activation, and deactivation of AMPactivated protein kinase. J Biol Chem 2006; 281(43): 32207-16
280. [280] Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 2011; 25(18): 1895-908
281. [281] Foretz M, Ancellin N, Andreelli F, et al. Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. Diabetes 2005; 54(5): 1331-9
282. [282] Leclerc I, Lenzner C, Gourdon L, et al. Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase. Diabetes 2001; 50(7): 1515-21
283. [283] Lochhead PA, Salt IP, Walker KS, Hardie DG, Sutherland C. 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 2000; 49(6): 896-903
284. [284] Bergeron R, Ren JM, Cadman KS, et al. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 2001; 281(6): E1340-6
285. [285] Long YC, Barnes BR, Mahlapuu M, et al. Role of AMP-activated protein kinase in the coordinated expression of genes controlling glucose and lipid metabolism in mouse white skeletal muscle. Diabetologia 2005; 48(11): 2354-64
286. [286] Rockl KS, Hirshman MF, Brandauer J, et al. Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. Diabetes 2007; 56(8): 2062-9
287. [287] Winder WW, Holmes BF, Rubink DS, et al. Activation of AMPactivated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 2000; 88(6): 2219-26
288. Viollet B, Athea Y, Mounier R, et al. AMPK: Lessons from transgenic and knockout animals. Front Biosci 2009; 14(19-44).
289. [289] Jorgensen SB, Wojtaszewski JF, Viollet B, et al. Effects of alpha-AMPK knockout on exercise-induced gene activation in mouse skeletal muscle. FASEB J 2005; 19(9): 1146-8
290. [290] O'Neill HM, Maarbjerg SJ, Crane JD, et al. AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc Natl Acad Sci USA 2011; 108(38): 16092-7
291. [291] Norrbom J, Sallstedt EK, Fischer H, et al. Alternative splice variant PGC-1alpha-b is strongly induced by exercise in human skeletal muscle. Am J Physiol Endocrinol Metab 2011; 301(6): E1092-8
292. [292] Suwa M, Nakano H, Kumagai S. Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J Appl Physiol 2003; 95(3): 960-8
293. [293] Tadaishi M, Miura S, Kai Y, et al. Effect of exercise intensity and AICAR on isoform-specific expressions of murine skeletal muscle PGC-1alpha mRNA: a role of beta(2)-adrenergic receptor activation. Am J Physiol Endocrinol Metab 2011; 300(2): E341-9
294. [294] Jager S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 2007; 104(29): 12017-22
295. [295] Leick L, Fentz J, Bienso RS, et al. PGC-1{alpha} is required for AICAR-induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle. Am J Physiol Endocrinol Metab 2010; 299(3): E456-65
296. [296] Narkar VA, Downes M, Yu RT, et al. AMPK and PPARdelta agonists are exercise mimetics. Cell 2008; 134(3): 405-15
297. [297] Raney MA, Yee AJ, Todd MK, Turcotte LP. AMPK activation is not critical in the regulation of muscle FA uptake and oxidation during low-intensity muscle contraction. Am J Physiol Endocrinol Metab 2005; 288(3): E592-8
298. [298] Fujii N, Ho RC, Manabe Y, et al. Ablation of AMP-activated protein kinase alpha2 activity exacerbates insulin resistance induced by high-fat feeding of mice. Diabetes 2008; 57(11): 2958-66
299. [299] Bergeron R, Previs SF, Cline GW, et al. Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 2001; 50(5): 1076-82
300. [300] Cool B, Zinker B, Chiou W, et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 2006; 3(6): 403-16
301. [301] Andreelli F, Foretz M, Knauf C, et al. Liver adenosine monophosphate-activated kinase-alpha2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin. Endocrinology 2006; 147(5): 2432-41
302. [302] Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 1995; 229(2): 558-65
303. [303] Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G. Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes 1991; 40(10): 1259-66
304. [304] Young ME, Radda GK, Leighton B. Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR--an activator of AMP-activated protein kinase. FEBS Lett 1996; 382(1-2): 43-7
305. [305] Buhl ES, Jessen N, Pold R, et al. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes 2002; 51(7): 2199-206
306. [306] Iglesias MA, Ye JM, Frangioudakis G, et al. AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 2002; 51(10): 2886-94
307. [307] Pold R, Jensen LS, Jessen N, et al. Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes 2005; 54(4): 928-34
308. [308] Song XM, Fiedler M, Galuska D, et al. 5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia 2002; 45(1): 56-65
309. [309] 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. Diabetologia 2004; 47(11): 2012-21
310. [310] Moreno D, Knecht E, Viollet B, Sanz P. A769662, a novel activator of AMP-activated protein kinase, inhibits non-proteolytic components of the 26S proteasome by an AMPK-independent mechanism. FEBS Lett 2008; 582(17): 2650-4
311. [311] Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 2007; 104(17): 7217-22
312. [312] Um JH, Park SJ, Kang H, et al. AMP-activated protein kinasedeficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2010; 59(3): 554-63
313. [313] Zang M, Xu S, Maitland-Toolan KA, et al. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 2006; 55(8): 2180-91
314. [314] 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 2010; 11(3): 213-9
315. [315] Canto C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009; 458(7241): 1056-60
316. [316] Zheng J, Ramirez VD. Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br J Pharmacol 2000; 130(5): 1115-23
317. [317] Hawley SA, Ross FA, Chevtzoff C, et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 2010; 11(6): 554-65
318. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348 Pt 3(607-14).
319. [319] Suwa M, Egashira T, Nakano H, Sasaki H, Kumagai S. Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo. J Appl Physiol 2006; 101(6): 1685-92
320. [320] Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108(8): 1167-74
321. [321] Kristensen JM, Larsen S, Helge JW, Dela F, Wojtaszewski JF. Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice. PLoS One 2013; 8(1): e53533
322. [322] Nicholls DG, Locke RM. Thermogenic mechanisms in brown fat. Physiol Rev 1984; 64(1): 1-64
323. [323] Frontini A, Cinti S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab 2010; 11(4): 253-6
324. Villena JA. In Obesity Epidemic; iConcept Press, 2014
325. [325] Kontani Y, Wang Y, Kimura K, et al. UCP1 deficiency increases susceptibility to diet-induced obesity with age. Aging Cell 2005; 4(3): 147-55
326. [326] Lowell BB, Hamann A, et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 1993; 366(6457): 740-2
327. [327] Castillo M, Hall JA, Correa-Medina M, et al. Disruption of thyroid hormone activation in type 2 deiodinase knockout mice causes obesity with glucose intolerance and liver steatosis only at thermoneutrality. Diabetes 2011; 60(4): 1082-9
328. [328] Marsili A, Aguayo-Mazzucato C, Chen T, et al. Mice with a targeted deletion of the type 2 deiodinase are insulin resistant and susceptible to diet induced obesity. PLoS One 2011; 6(6): e20832
329. [329] Prpic V, Watson PM, Frampton IC, et al. Adaptive changes in adipocyte gene expression differ in AKR/J and SWR/J mice during diet-induced obesity. J Nutr 2002; 132(11): 3325-32
330. [330] Xue B, Coulter A, Rim JS, Koza RA, Kozak LP. Transcriptional synergy and the regulation of Ucp1 during brown adipocyte induction in white fat depots. Mol Cell Biol 2005; 25(18): 8311-22
331. [331] Auffret J, Viengchareun S, Carre N, et al. Beige differentiation of adipose depots in mice lacking prolactin receptor protects against high-fat-diet-induced obesity. FASEB J 2012; 26(9): 3728-37
332. [332] Cederberg A, Gronning LM, Ahren B, et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and dietinduced insulin resistance. Cell 2001; 106(5): 563-73
333. [333] Leonardsson G, Steel JH, Christian M, et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci USA 2004; 101(22): 8437-42
334. [334] Scime A, Grenier G, Huh MS, et al. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1alpha. Cell Metab 2005; 2(5): 283-95
335. [335] Seale P, Conroe HM, Estall J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 2011; 121(1): 96-105
336. [336] Strom K, Hansson O, Lucas S, et al. Attainment of brown adipocyte features in white adipocytes of hormone-sensitive lipase null mice. PLoS One 2008; 3(3): e1793
337. [337] Toh SY, Gong J, Du G, et al. Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice. PLoS One 2008; 3(8): e2890
338. [338] Cypess AM, Lehman S, Williams G, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360(15): 1509-17
339. [339] van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009; 360(15): 1500-8
340. [340] Virtanen KA, Lidell ME, Orava J, et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360(15): 1518-25
341. [341] Zingaretti MC, Crosta F, Vitali A, et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009; 23(9): 3113-20
342. [342] Wu J, Bostrom P, Sparks LM, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150(2): 366-76
343. [343] Saito M, Okamatsu-Ogura Y, Matsushita M, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009; 58(7): 1526-31
344. [344] Bloom JD, Dutia MD, Johnson BD, et al. Disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316,243). A potent betaadrenergic agonist virtually specific for beta 3 receptors. A promising antidiabetic and antiobesity agent. J Med Chem 1992; 35(16): 3081-4
345. [345] Kato H, Ohue M, Kato K, et al. Mechanism of amelioration of insulin resistance by beta3-adrenoceptor agonist AJ-9677 in the KK-Ay/Ta diabetic obese mouse model. Diabetes 2001; 50(1): 113-22
346. [346] Umekawa T, Yoshida T, Sakane N, et al. Anti-obesity and antidiabetic effects of CL316,243, a highly specific beta 3-adrenoceptor agonist, in Otsuka Long-Evans Tokushima Fatty rats: induction of uncoupling protein and activation of glucose transporter 4 in white fat. Eur J Endocrinol 1997; 136(4): 429-37
347. [347] Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007; 293(2): E444-52
348. [348] Cypess AM, Chen YC, Sze C, et al. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc Natl Acad Sci USA 2012; 109(25): 10001-5
349. [349] Carmona MC, Louche K, Lefebvre B, et al. S 26948: a new specific peroxisome proliferator activated receptor gamma modulator with potent antidiabetes and antiatherogenic effects. Diabetes 2007; 56(11): 2797-808
350. [350] Petrovic N, Walden TB, Shabalina IG, et al. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) 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(10): 7153-64
351. [351] Sell H, Berger JP, Samson P, et al. Peroxisome proliferatoractivated receptor gamma agonism increases the capacity for sympathetically mediated thermogenesis in lean and ob/ob mice. Endocrinology 2004; 145(8): 3925-34
352. [352] Bostrom P, Wu J, Jedrychowski MP, et al. A PGC1-alphadependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481(7382): 463-8
353. [353] Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006; 116(3): 590-7
354. [354] Lee CH, Olson P, Hevener A, et al. PPARdelta regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci USA 2006; 103(9): 3444-9
355. [355] Tanaka T, Yamamoto J, Iwasaki S, et al. Activation of peroxisome proliferator-activated receptor delta induces fatty acid betaoxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci USA 2003; 100(26): 15924-9
356. [356] Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest 2004; 114(11): 1564-76
357. [357] Oliver WR, Jr., Shenk JL, Snaith MR, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 2001; 98(9): 5306-11
358. [358] Ooi EM, Watts GF, Sprecher DL, Chan DC, Barrett PH. Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity. J Clin Endocrinol Metab 2011; 96(10): E1568-76
359. [359] Riserus U, Sprecher D, Johnson T, et al. Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 2008; 57(2): 332-9
360. [360] Bays HE, Schwartz S, Littlejohn T, 3rd, et al. MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J Clin Endocrinol Metab 2011; 96(9): 2889-97
361. [361] Luo J, Sladek R, Carrier J, et al. Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol Cell Biol 2003; 23(22): 7947-56
362. [362] Rangwala SM, Wang X, Calvo JA, et al. Estrogen-related receptor gamma is a key regulator of muscle mitochondrial activity and oxidative capacity. J Biol Chem 2010; 285(29): 22619-29
363. [363] Busch BB, Stevens WC, Jr., Martin R, et al. Identification of a selective inverse agonist for the orphan nuclear receptor estrogenrelated receptor alpha. J Med Chem 2004; 47(23): 5593-6
364. [364] Mootha VK, Handschin C, Arlow D, et al. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proc Natl Acad Sci USA 2004; 101(17): 6570-5
365. [365] Peng L, Gao X, Duan L, et al. Identification of pyrido[1,2-alpha]pyrimidine-4-ones as new molecules improving the transcriptional functions of estrogen-related receptor alpha. J Med Chem 2011; 54(21): 7729-33
366. [366] Patch RJ, Searle LL, Kim AJ, et al. Identification of diaryl etherbased ligands for estrogen-related receptor alpha as potential antidiabetic agents. J Med Chem 2011; 54(3): 788-808
367. [367] Herzog B, Cardenas J, Hall RK, et al. Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem 2006; 281(1): 99-106