PGC-1α activation: a therapeutic target for type 2 diabetes?

  • Daixiu Yuan
  • Dingfu Xiao
  • Qian Gao
  • Liming ZengEmail author
Review Article


Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has gained popularity as a very attractive target for diabetic therapies due to its role in lipid and glucose metabolism. Pharmacological activation of PGC-1α is thought to elicit health benefits. However, this notion has been questioned by increasing evidence, which suggests that insulin resistant is exacerbated when PGC-1α expression is far beyond normal physiological limits and is prevented under the condition of PGC-1α deficiency. This narrative review suggests that PGC-1α, as a master metabolic regulator, exerts roles in insulin sensitivity in a tissue-specific manner and in a physical activity/age-dependent fashion. When using PGC-1α as a target for therapeutic strategies against insulin resistance and T2DM, we should take these factors into consideration.

Level of evidence: Level V, narrative review.


Peroxisome proliferator-activated receptor-γ coactivator-1α Type 2 diabetes Insulin resistance Drug therapy 



This study was funded by the Project of Science and Technology of Jiangxi Province (20151BBF60008) and the Major Project of Education Department in Hunan (16A096).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Boden G, Shulman GI (2002) Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Investig 32:14–23. CrossRefGoogle Scholar
  2. 2.
    Yao K, Duan Y, Li F, Tan B, Hou Y, Wu G, Yin Y (2016) Leucine in obesity: therapeutic prospects. Trends Pharmacol Sci 37:714–727. CrossRefPubMedGoogle Scholar
  3. 3.
    Coughlan KA, Valentine RJ, Ruderman NB, Saha AK (2014) AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes 7:241–253. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Puigserver P, Wu ZD, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839. CrossRefPubMedGoogle Scholar
  5. 5.
    Esterbauer H, Oberkofler H, Krempler F, Patsch W (1999) Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1) gene: cDNA sequence, genomic organization, chromosomal localization, and tissue expression. Genomics 62:98–102. CrossRefPubMedGoogle Scholar
  6. 6.
    Finck BN, Kelly DP (2006) PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Investig 116:615–622. CrossRefPubMedGoogle Scholar
  7. 7.
    Lin J, Wu H, Tarr PT, Zhang CY, Wu ZD, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418:797–801. CrossRefPubMedGoogle Scholar
  8. 8.
    Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131–138. CrossRefPubMedGoogle Scholar
  9. 9.
    Corona J, Duchen M (2015) PPAR gamma and PGC-1 alpha as therapeutic targets in parkinson’s. Neurochem Res 40:308–316. CrossRefPubMedGoogle Scholar
  10. 10.
    Yoon JC, Xu G, Deeney JT, Yang S-N, Rhee J, Puigserver P, Levens AR, Yang R, Zhang C-Y, Lowell BB, Berggren P-O, Newgard CB, Bonner-Weir S, Weir G, Spiegelman BM (2003) Suppression of β cell energy metabolism and insulin release by PGC-1α. Dev Cell 5:73–83. CrossRefPubMedGoogle Scholar
  11. 11.
    Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, Kelly DP, Holloszy JO (2002) Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J 16:1879–1886. CrossRefPubMedGoogle Scholar
  12. 12.
    Wu H, Deng X, Shi Y, Su Y, Wei J, Duan H (2016) PGC-1α, glucose metabolism and type 2 diabetes mellitus. J Endocrinol 229:R99–R115. CrossRefPubMedGoogle Scholar
  13. 13.
    Summermatter S, Shui G, Maag D, Santos G, Wenk MR, Handschin C (2013) PGC-1α improves glucose homeostasis in skeletal muscle in an activity-dependent manner. Diabetes 62:85–95. CrossRefPubMedGoogle Scholar
  14. 14.
    Choi CS, Befroy DE, Codella R, Kim S, Reznick RM, Hwang YJ, Liu ZX, Lee HY, Distefano A, Samuel VT, Zhang D, Cline GW, Handschin C, Lin J, Petersen KF, Spiegelman B, Shulman GI (2008) Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc Natl Acad Sci USA 105:19926–19931. CrossRefPubMedGoogle Scholar
  15. 15.
    Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, Mootha VK, Jager S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki AM, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119:121–135. CrossRefPubMedGoogle Scholar
  16. 16.
    Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, Boudina S, Courtois M, Wozniak DF, Sambandam N, Bernal-Mizrachi C, Chen Z, Holloszy JO, Medeiros DM, Schmidt RE, Saffitz JE, Abel ED, Semenkovich CF, Kelly DP (2005) PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3:e101. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Russell AP, Feilchenfeldt J, Schreiber S, Praz M, Crettenand A, Gobelet C, Meier CA, Bell DR, Kralli A, Giacobino JP, Deriaz O (2003) Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 52:2874–2881. CrossRefPubMedGoogle Scholar
  18. 18.
    Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E (2007) Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 4:485–494. CrossRefGoogle Scholar
  19. 19.
    Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D (2003) Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423:550. CrossRefPubMedGoogle Scholar
  20. 20.
    Sutherland LN, Bomhof MR, Capozzi LC, Basaraba SA, Wright DC (2009) Exercise and adrenaline increase PGC-1α mRNA expression in rat adipose tissue. J Physiol 587:1607–1617. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Herzig S, Long FX, Jhala US, Hedrick S, Quinn R, Bauer A, Rudolph D, Schutz G, Yoon C, Puigserver P, Spiegelman B, Montminy M (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413:179–183. CrossRefPubMedGoogle Scholar
  22. 22.
    Wu ZD, Huang XM, Feng YJ, Handschin C, Feng Y, Gullicksen PS, Bare O, Labow M, Spiegelman B, Stevenson SC (2006) Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1α transcription and mitochondrial biogenesis in muscle cells. Proc Natl Acad Sci USA 103:14379. CrossRefPubMedGoogle Scholar
  23. 23.
    Handschin C, Rhee J, Lin JD, Tarr PT, Spiegelman BM (2003) An autoregulatory loop controls peroxisome proliferator-activated receptor γ coactivator 1α expression in muscle. Proc Natl Acad Sci USA 100:7111–7116. CrossRefPubMedGoogle Scholar
  24. 24.
    Teyssier C, Ma H, Emter R, Kralli A, Stallcup MR (2005) Activation of nuclear receptor coactivator PGC-1alpha by arginine methylation. Genes Dev 19:1466–1473. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Lerin C, Rodgers JT, Kalume DE, Kim SH, Pandey A, Puigserver P (2006) GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Cell Metab 3:429–438. CrossRefPubMedGoogle Scholar
  26. 26.
    Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1 alpha and SIRT1. Nature 434:113–118. CrossRefPubMedGoogle Scholar
  27. 27.
    Waldman M, Cohen K, Yadin D, Nudelman V, Gorfil D, Laniado-Schwartzman M, Kornwoski R, Aravot D, Abraham NG, Arad M, Hochhauser E (2018) Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving ‘SIRT1 and PGC-1alpha’. Cardiovasc Diabetol 17:111. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hu N, Ren J, Zhang YM (2016) Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α. Oncotarget 7:76398–76414. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Li X, Monks B, Ge Q, Birnbaum MJ (2007) Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature 447:1012–1016. CrossRefPubMedGoogle Scholar
  30. 30.
    Popov DV, Lysenko EA, Kuzmin IV, Vinogradova V, Grigoriev AI (2015) Regulation of PGC-1a isoform expression in skeletal muscles. Acta Nat 7:48–59Google Scholar
  31. 31.
    Wu Z, Boss O (2007) Targeting PGC-1 alpha to control energy homeostasis. Expert Opin Ther Targets 11:1329–1338. CrossRefPubMedGoogle Scholar
  32. 32.
    Michael LF, Wu Z, Cheatham R, Puigserver P, Adelmant G, Lehman JJ, Kelly DP, Spiegelman B (2001) Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci USA 98:3820–3825. CrossRefPubMedGoogle Scholar
  33. 33.
    Kong X, Wang R, Xue Y, Liu X, Zhang H, Chen Y, Fang F, Chang Y (2010) Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 5:e11707. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Huss JM, Kopp RP, Kelly DP (2002) Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma: identification of novel leucine-rich interaction motif within PGC-1alpha. J Biol Chem 277:40265–40274. CrossRefPubMedGoogle Scholar
  35. 35.
    Vega RB, Huss JM, Kelly DP (2000) The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 20:1868–1876. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Wu ZD, Puigserver P, Andersson U, Zhang CY, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124. CrossRefPubMedGoogle Scholar
  37. 37.
    Barroso WA, Victorino VJ, Jeremias IC, Petroni RC, Ariga SKK, Salles TA, Barbeiro DF, de Lima TM, de Souza HP (2018) High-fat diet inhibits PGC-1alpha suppressive effect on NFkappaB signaling in hepatocytes. Eur J Nutr 57:1891–1900. CrossRefPubMedGoogle Scholar
  38. 38.
    Lee J, Salazar Hernandez MA, Auen T, Mucka P, Lee J, Ozcan U (2018) PGC-1alpha functions as a co-suppressor of XBP1s to regulate glucose metabolism. Mol Metab 7:119–131. CrossRefPubMedGoogle Scholar
  39. 39.
    Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273. CrossRefPubMedGoogle Scholar
  40. 40.
    Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ (2003) 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 100:8466–8471. CrossRefPubMedGoogle Scholar
  41. 41.
    Hammarstedt A, Jansson PA, Wesslau C, Yang X, Smith U (2003) Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance. Biochem Biophys Res Commun 301:578–582. CrossRefPubMedGoogle Scholar
  42. 42.
    Kleiner S, Mepani RJ, Laznik D, Ye L, Jurczak MJ, Jornayvaz FR, Estall JL, Chatterjee Bhowmick D, Shulman GI, Spiegelman BM (2012) Development of insulin resistance in mice lacking PGC-1alpha in adipose tissues. Proc Natl Acad Sci USA 109:9635–9640. CrossRefPubMedGoogle Scholar
  43. 43.
    Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Palomba L, Cantoni O, Clementi E, Moncada S (2006) TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J Clin Investig 116:2791–2798. CrossRefPubMedGoogle Scholar
  44. 44.
    Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT (2009) Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci USA 106:20405–20410. CrossRefPubMedGoogle Scholar
  45. 45.
    Handschin C (2009) The biology of PGC-1alpha and its therapeutic potential. Trends Pharmacol Sci 30:322–329. CrossRefPubMedGoogle Scholar
  46. 46.
    Besseiche A, Riveline JP, Gautier JF, Breant B, Blondeau B (2015) Metabolic roles of PGC-1alpha and its implications for type 2 diabetes. Diabetes Metab 41:347–357. CrossRefPubMedGoogle Scholar
  47. 47.
    Ying F, Zhang L, Bu G, Xiong Y, Zuo B (2016) Muscle fiber-type conversion in the transgenic pigs with overexpression of PGC1alpha gene in muscle. Biochem Biophys Res Commun 480:669–674. CrossRefPubMedGoogle Scholar
  48. 48.
    Benton CR, Nickerson JG, Lally J, Han XX, Holloway GP, Glatz JF, Luiken JJ, Graham TE, Heikkila JJ, Bonen A (2008) Modest PGC-1alpha overexpression in muscle in vivo is sufficient to increase insulin sensitivity and palmitate oxidation in subsarcolemmal, not intermyofibrillar, mitochondria. J Biol Chem 283:4228–4240. CrossRefPubMedGoogle Scholar
  49. 49.
    Wende AR, Huss JM, Schaeffer PJ, Giguere V, Kelly DP (2005) PGC-1alpha coactivates PDK4 gene expression via the orphan nuclear receptor ERRalpha: a mechanism for transcriptional control of muscle glucose metabolism. Mol Cell Biol 25:10684–10694. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Mormeneo E, Jimenez-Mallebrera C, Palomer X, De Nigris V, Vazquez-Carrera M, Orozco A, Nascimento A, Colomer J, Lerin C, Gomez-Foix AM (2012) PGC-1alpha induces mitochondrial and myokine transcriptional programs and lipid droplet and glycogen accumulation in cultured human skeletal muscle cells. PLoS One 7:e29985. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Wende AR, Schaeffer PJ, Parker GJ, Zechner C, Han DH, Chen MM, Hancock CR, Lehman JJ, Huss JM, McClain DA, Holloszy JO, Kelly DP (2007) A role for the transcriptional coactivator PGC-1alpha in muscle refueling. J Biol Chem 282:36642–36651. CrossRefPubMedGoogle Scholar
  52. 52.
    Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK, Yan Z, Spiegelman BM (2007) Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J Biol Chem 282:30014–30021. CrossRefPubMedGoogle Scholar
  53. 53.
    Handschin C, Choi CS, Chin S, Kim S, Kawamori D, Kurpad AJ, Neubauer N, Hu J, Mootha VK, Kim YB, Kulkarni RN, Shulman GI, Spiegelman BM (2007) Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle–pancreatic beta cell crosstalk. J Clin Investig 117:3463–3474. CrossRefPubMedGoogle Scholar
  54. 54.
    Eisele PS, Salatino S, Sobek J, Hottiger MO, Handschin C (2013) The peroxisome proliferator-activated receptor gamma coactivator 1alpha/beta (PGC-1) coactivators repress the transcriptional activity of NF-kappaB in skeletal muscle cells. J Biol Chem 288:2246–2260. CrossRefPubMedGoogle Scholar
  55. 55.
    Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP (2000) Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Investig 106:847–856. CrossRefPubMedGoogle Scholar
  56. 56.
    Russell LK, Mansfield CM, Lehman JJ, Kovacs A, Courtois M, Saffitz JE, Medeiros DM, Valencik ML, McDonald JA, Kelly DP (2004) Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circ Res 94:525–533. CrossRefPubMedGoogle Scholar
  57. 57.
    Sonoda J, Mehl IR, Chong LW, Nofsinger RR, Evans RM (2007) PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc Natl Acad Sci USA 104:5223–5228. CrossRefPubMedGoogle Scholar
  58. 58.
    Lelliott CJ, Medina-Gomez G, Petrovic N, Kis A, Feldmann HM, Bjursell M, Parker N, Curtis K, Campbell M, Hu P, Zhang D, Litwin SE, Zaha VG, Fountain KT, Boudina S, Jimenez-Linan M, Blount M, Lopez M, Meirhaeghe A, Bohlooly YM, Storlien L, Stromstedt M, Snaith M, Oresic M, Abel ED, Cannon B, Vidal-Puig A (2006) Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol 4:e369. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Nikolic N, Rhedin M, Rustan AC, Storlien L, Thoresen GH, Stromstedt M (2012) Overexpression of PGC-1alpha increases fatty acid oxidative capacity of human skeletal muscle cells. Biochem Res Int 2012:714074. CrossRefPubMedGoogle Scholar
  60. 60.
    Zhang LN, Zhou HY, Fu YY, Li YY, Wu F, Gu M, Wu LY, Xia CM, Dong TC, Li JY, Shen JK, Li J (2013) Novel small-molecule PGC-1a transcriptional regulator with beneficial effects on diabetic db/db mice. Diabetes 62:1297–1307. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Handschin C, Spiegelman BM (2008) The role of exercise and PGC1alpha in inflammation and chronic disease. Nature 454:463–469. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Uldry M, Yang W, St-Pierre J, Lin J, Seale P, Spiegelman BM (2006) Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab 3:333–341. CrossRefPubMedGoogle Scholar
  63. 63.
    Supruniuk E, Miklosz A, Chabowski A (2017) The implication of PGC-1alpha on fatty acid transport across plasma and mitochondrial membranes in the insulin sensitive tissues. Front Physiol 8:923. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Pettersson-Klein AT, Izadi M, Ferreira DMS, Cervenka I, Correia JC, Martinez-Redondo V, Southern M, Cameron M, Kamenecka T, Agudelo LZ, Porsmyr-Palmertz M, Martens U, Lundgren B, Otrocka M, Jenmalm-Jensen A, Griffin PR, Ruas JL (2018) Small molecule PGC-1α1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration. Mol Metab 9:28–42. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Tadaishi M, Miura S, Kai Y, Kano Y, Oishi Y, Ezaki O (2011) Skeletal muscle-specific expression of PGC-1alpha-b, an exercise-responsive isoform, increases exercise capacity and peak oxygen uptake. PLoS One 6:e28290. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, Spiegelman BM (2012) FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 26:271–281. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Pan D, Fujimoto M, Lopes A, Wang YX (2009) Twist-1 is a PPARdelta-inducible, negative feedback regulator of PGC-1alpha in brown fat metabolism. Cell 137:73–86. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM (2012) A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–472. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Tiraby C, Tavernier G, Lefort C, Larrouy D, Bouillaud F, Ricquier D, Langin D (2003) Acquirement of brown fat cell features by human white adipocytes. J Biol Chem 278:33370–33376. CrossRefPubMedGoogle Scholar
  70. 70.
    Lin J, Tarr PT, Yang R, Rhee J, Puigserver P, Newgard CB, Spiegelman BM (2003) PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem 278:30843–30848. CrossRefPubMedGoogle Scholar
  71. 71.
    Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ, Spiegelman BM (2003) Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci USA 100:4012–4017. CrossRefPubMedGoogle Scholar
  72. 72.
    Koo SH, Satoh H, Herzig S, Lee CH, Hedrick S, Kulkarni R, Evans RM, Olefsky J, Montminy M (2004) PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat Med 10:530–534. CrossRefPubMedGoogle Scholar
  73. 73.
    Liang H, Balas B, Tantiwong P, Dube J, Goodpaster BH, O’Doherty RM, DeFronzo RA, Richardson A, Musi N, Ward WF (2009) Whole body overexpression of PGC-1alpha has opposite effects on hepatic and muscle insulin sensitivity. Am J Physiol Endocrinol Metab 296:E945–E954. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Tamura Y, Ogihara T, Uchida T, Ikeda F, Kumashiro N, Nomiyama T, Sato F, Hirose T, Tanaka Y, Mochizuki H, Kawamori R, Watada H (2007) Amelioration of glucose tolerance by hepatic inhibition of nuclear factor kappaB in db/db mice. Diabetologia 50:131–141. CrossRefPubMedGoogle Scholar
  75. 75.
    Xu J, Li Y, Lou M, Xia W, Liu Q, Xie G, Liu L, Liu B, Yang J, Qin M (2018) Baicalin regulates SirT1/STAT3 pathway and restrains excessive hepatic glucose production. Pharmacol Res 136:62–73. CrossRefPubMedGoogle Scholar
  76. 76.
    Estall JL, Ruas JL, Choi CS, Laznik D, Badman M, Maratos-Flier E, Shulman GI, Spiegelman BM (2009) PGC-1alpha negatively regulates hepatic FGF21 expression by modulating the heme/Rev-Erb(alpha) axis. Proc Natl Acad Sci USA 106:22510–22515. CrossRefPubMedGoogle Scholar
  77. 77.
    Sharabi K, Lin H, Tavares CDJ, Dominy JE, Camporez JP, Perry RJ, Schilling R, Rines AK, Lee J, Hickey M, Bennion M, Palmer M, Nag PP, Bittker JA, Perez J, Jedrychowski MP, Ozcan U, Gygi SP, Kamenecka TM, Shulman GI, Schreiber SL, Griffin PR, Puigserver P (2017) Selective chemical inhibition of PGC-1alpha gluconeogenic activity ameliorates type 2 diabetes. Cell 169:148.e115–160.e115. CrossRefGoogle Scholar
  78. 78.
    Ling C, Del Guerra S, Lupi R, Ronn T, Granhall C, Luthman H, Masiello P, Marchetti P, Groop L, Del Prato S (2008) Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51:615–622. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Valtat B, Riveline JP, Zhang P, Singh-Estivalet A, Armanet M, Venteclef N, Besseiche A, Kelly DP, Tronche F, Ferre P, Gautier JF, Breant B, Blondeau B (2013) Fetal PGC-1alpha overexpression programs adult pancreatic beta-cell dysfunction. Diabetes 62:1206–1216. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Zhang P, Liu C, Zhang C, Zhang Y, Shen P, Zhang J, Zhang CY (2005) Free fatty acids increase PGC-1alpha expression in isolated rat islets. FEBS Lett 579:1446–1452. CrossRefPubMedGoogle Scholar
  81. 81.
    Besseiche A, Riveline JP, Delavallée L, Foufelle F, Gautier JF, Blondeau B (2017) Oxidative and energetic stresses mediate beta-cell dysfunction induced by PGC-1α. Diabetes Metab 44:45–54. CrossRefPubMedGoogle Scholar
  82. 82.
    Sun LL, Jiang BG, Li WT, Zou JJ, Shi YQ, Liu ZM (2011) MicroRNA-15a positively regulates insulin synthesis by inhibiting uncoupling protein-2 expression. Diabetes Res Clin Pr 91:94–100. CrossRefGoogle Scholar
  83. 83.
    De Souza CT, Gasparetti AL, Pereira-da-Silva M, Araujo EP, Carvalheira JB, Saad MJ, Boschero AC, Carneiro EM, Velloso LA (2003) Peroxisome proliferator-activated receptor gamma coactivator-1-dependent uncoupling protein-2 expression in pancreatic islets of rats: a novel pathway for neural control of insulin secretion. Diabetologia 46:1522–1531. CrossRefPubMedGoogle Scholar
  84. 84.
    Oberkofler H, Klein K, Felder TK, Krempler F, Patsch W (2006) Role of peroxisome proliferator-activated receptor-gamma coactivator-1alpha in the transcriptional regulation of the human uncoupling protein 2 gene in INS-1E cells. Endocrinology 147:966–976. CrossRefPubMedGoogle Scholar
  85. 85.
    Santos RF, Mondon CE, Reaven GM, Azhar S (1989) Effects of exercise training on the relationship between insulin binding and insulin-stimulated tyrosine kinase-activity in rat skeletal-muscle. Metabolism 38:376–386. CrossRefPubMedGoogle Scholar
  86. 86.
    Matiello R, Fukui RT, Silva MER, Rocha DM, Wajchenberg BL, Azhar S, Santos RF (2010) Differential regulation of PGC-1α expression in rat liver and skeletal muscle in response to voluntary running. Nutr Metab 7:36. CrossRefGoogle Scholar
  87. 87.
    Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E, Gustafsson T (2004) PGC-1 alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol 96:189–194. CrossRefPubMedGoogle Scholar
  88. 88.
    Sriwijitkamol A, Coletta DK, Wajcberg E, Balbontin GB, Reyna SM, Barrientes J, Eagan PA, Jenkinson CP, Cersosimo E, DeFronzo RA, Sakamoto K, Musi N (2007) Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes - A time-course and dose-response study. Diabetes 56:836–848. CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Taylor EB, Lamb JD, Hurst RW, Chesser DG, Ellingson WJ, Greenwood LJ, Porter BB, Herway ST, Winder WW (2005) Endurance training increases skeletal muscle LKB1 and PGC-1 alpha protein abundance: effects of time and intensity. Am J Physiol Endocrinol Metab 289:E960–E968. CrossRefPubMedGoogle Scholar
  90. 90.
    Eisele PS, Handschin C (2014) Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology. Semin Immunopathol 36:27–53. CrossRefPubMedGoogle Scholar
  91. 91.
    Matsukawa T, Motojima H, Sato Y, Takahashi S, Villareal MO, Isoda H (2017) Upregulation of skeletal muscle PGC-1alpha through the elevation of cyclic AMP levels by Cyanidin-3-glucoside enhances exercise performance. Sci Rep 7:44799. CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Miura S, Kawanaka K, Kai Y, Tamura M, Goto M, Shiuchi T, Minokoshi Y, Ezaki O (2007) An increase in murine skeletal muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA in response to exercise is mediated by beta-adrenergic receptor activation. Endocrinology 148:3441. CrossRefPubMedGoogle Scholar
  93. 93.
    Calvo JA, Daniels TG, Wang X, Paul A, Lin J, Spiegelman BM, Stevenson SC, Rangwala SM (2008) Muscle-specific expression of PPARgamma coactivator-1alpha improves exercise performance and increases peak oxygen uptake. J Appl Physiol (1985) 104:1304–1312. CrossRefGoogle Scholar
  94. 94.
    Bonen A (2009) PGC-1alpha-induced improvements in skeletal muscle metabolism and insulin sensitivity. Appl Physiol Nutr Metab 34:307–314. CrossRefPubMedGoogle Scholar
  95. 95.
    Rowe GC, El-Khoury R, Patten IS, Rustin P, Arany Z (2012) PGC-1alpha is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle. PLoS One 7:e41817. CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Adams SH, Hoppel CL, Lok KH, Zhao L, Wong SW, Minkler PE, Hwang DH, Newman JW, Garvey WT (2009) Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic african-american women. J Nutr 139:1073–1081. CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7:45–56. CrossRefPubMedGoogle Scholar
  98. 98.
    Ling C, Poulsen P, Carlsson E, Ridderstrale M, Almgren P, Wojtaszewski J, Beck-Nielsen H, Groop L, Vaag A (2004) Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. J Clin Invest 114:1518–1526. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Handschin C, Spiegelman BM (2006) Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27:728–735. CrossRefPubMedGoogle Scholar
  100. 100.
    Sczelecki S, Besse-Patin A, Abboud A, Kleiner S, Laznik-Bogoslavski D, Wrann CD, Ruas JL, Haibe-Kains B, Estall JL (2014) Loss of Pgc-1alpha expression in aging mouse muscle potentiates glucose intolerance and systemic inflammation. Am J Physiol Endocrinol Metab 306:E157–E167. CrossRefPubMedGoogle Scholar
  101. 101.
    Leick L, Lyngby SS, Wojtaszewski JF, Pilegaard H (2010) PGC-1alpha is required for training-induced prevention of age-associated decline in mitochondrial enzymes in mouse skeletal muscle. Exp Gerontol 45:336–342. CrossRefPubMedGoogle Scholar
  102. 102.
    Leick L, Wojtaszewski JF, Johansen ST, Kiilerich K, Comes G, Hellsten Y, Hidalgo J, Pilegaard H (2008) PGC-1alpha is not mandatory for exercise- and training-induced adaptive gene responses in mouse skeletal muscle. Am J Physiol Endocrinol Metab 294:E463. CrossRefPubMedGoogle Scholar
  103. 103.
    Miura S, Kai Y, Ono M, Ezaki O (2003) Overexpression of peroxisome proliferator-activated receptor gamma coactivator-1alpha down-regulates GLUT4 mRNA in skeletal muscles. J Biol Chem 278:31385. CrossRefPubMedGoogle Scholar
  104. 104.
    Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB, Williams RS, Yan Z (2005) Exercise stimulates Pgc-1 alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem 280:19587–19593. CrossRefPubMedGoogle Scholar
  105. 105.
    Oliveira RLGS, Ueno M, de Souza CT, Pereira-da-Silva M, Gasparetti AL, Bezzera RMN, Alberici LC, Vercesi AE, Saad MJA, Velloso LA (2004) Cold-induced PGC-1 alpha expression modulates muscle glucose uptake through an insulin receptor/Akt-independent, AMPK-dependent pathway. Am J Physiol Endocrinol Metab 287:E686–E695. CrossRefPubMedGoogle Scholar
  106. 106.
    Benton CR, Holloway GP, Han XX, Yoshida Y, Snook LA, Lally J, Glatz JF, Luiken JJ, Chabowski A, Bonen A (2010) Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats. Diabetologia 53:2008–2019. CrossRefPubMedGoogle Scholar
  107. 107.
    Arany Z, He HM, Lin JD, Hoyer K, Handschin C, Toka O, Ahmad F, Matsui T, Chin S, Wu PH, Rybkin II, Shelton JM, Manieri M, Cinti S, Schoen FJ, Bassel-Duby R, Rosenzweig A, Ingwall JS, Spiegelman BM (2005) Transcriptional coactivator PGC-1 alpha controls the energy state and contractile function of cardiac muscle. Cell Metab 1:259–271. CrossRefPubMedGoogle Scholar
  108. 108.
    Rowe GC, Patten IS, Zsengeller ZK, El-Khoury R, Okutsu M, Bampoh S, Koulisis N, Farrell C, Hirshman MF, Yan Z, Goodyear LJ, Rustin P, Arany Z (2013) Disconnecting mitochondrial content from respiratory chain capacity in PGC-1-deficient skeletal muscle. Cell Rep 3:1449–1456. CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Zechner C, Lai L, Zechner JF, Geng TY, Yan Z, Rumsey JW, Collia D, Chen ZJ, Wozniak DF, Leone TC, Kelly DP (2010) Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metab 12:633–642. CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Oropeza D, Jouvet N, Bouyakdan K, Perron G, Ringuette LJ, Philipson LH, Kiss RS, Poitout V, Alquier T, Estall JL (2015) PGC-1 coactivators in beta-cells regulate lipid metabolism and are essential for insulin secretion coupled to fatty acids. Mol Metab 4:811–822. CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Pardo R, Enguix N, Lasheras J, Feliu JE, Kralli A, Villena JA (2011) Rosiglitazone-induced mitochondrial biogenesis in white adipose tissue is independent of peroxisome proliferator-activated receptor γ coactivator-1α. PLoS One 6:e26989. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Daixiu Yuan
    • 1
  • Dingfu Xiao
    • 2
  • Qian Gao
    • 2
  • Liming Zeng
    • 3
    Email author
  1. 1.Department of MedicineJishou UniversityJishouChina
  2. 2.College of Animal Science and TechnologyHunan Agricultural UniversityChangshaChina
  3. 3.Science College of Jiangxi Agricultural UniversityNanchangChina

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