All Title Author
Keywords Abstract

PLOS ONE  2011 

Rosiglitazone-Induced Mitochondrial Biogenesis in White Adipose Tissue Is Independent of Peroxisome Proliferator-Activated Receptor γ Coactivator-1α

DOI: 10.1371/journal.pone.0026989

Full-Text   Cite this paper   Add to My Lib


Background Thiazolidinediones, a family of insulin-sensitizing drugs commonly used to treat type 2 diabetes, are thought to exert their effects in part by promoting mitochondrial biogenesis in white adipose tissue through the transcriptional coactivator PGC-1α (Peroxisome Proliferator-Activated Receptor γ Coactivator-1α). Methodology/Principal Findings To assess the role of PGC-1α in the control of rosiglitazone-induced mitochondrial biogenesis, we have generated a mouse model that lacks expression of PGC-1α specifically in adipose tissues (PGC-1α-FAT-KO mice). We found that expression of genes encoding for mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle or fatty acid oxidation, was similar in white adipose tissue of wild type and PGC-1α-FAT-KO mice. Furthermore, the absence of PGC-1α did not prevent the positive effect of rosiglitazone on mitochondrial gene expression or biogenesis, but it precluded the induction by rosiglitazone of UCP1 and other brown fat-specific genes in white adipose tissue. Consistent with the in vivo findings, basal and rosiglitazone-induced mitochondrial gene expression in 3T3-L1 adipocytes was unaffected by the knockdown of PGC-1α but it was impaired when PGC-1β expression was knockdown by the use of specific siRNA. Conclusions/Significance These results indicate that in white adipose tissue PGC-1α is dispensable for basal and rosiglitazone-induced mitochondrial biogenesis but required for the rosiglitazone-induced expression of UCP1 and other brown adipocyte-specific markers. Our study suggests that PGC-1α is important for the appearance of brown adipocytes in white adipose tissue. Our findings also provide evidence that PGC-1β and not PGC-1α regulates basal and rosiglitazone-induced mitochondrial gene expression in white adipocytes.


[1]  Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55: Suppl 2S9–S15.
[2]  Bogacka I, Xie H, Bray GA, Smith SR (2005) Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54: 1392–1399.
[3]  Dahlman I, Forsgren M, Sjogren A, Nordstrom EA, Kaaman M, et al. (2006) 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 55: 1792–1799.
[4]  Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51: 2944–2950.
[5]  Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, et al. (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 U S A 100: 8466–8471.
[6]  Heilbronn LK, Gan SK, Turner N, Campbell LV, Chisholm DJ (2007) Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects. J Clin Endocrinol Metab 92: 1467–1473.
[7]  Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, et al. (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34: 267–273.
[8]  Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350: 664–671.
[9]  Choo HJ, Kim JH, Kwon OB, Lee CS, Mun JY, et al. (2006) Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 49: 784–791.
[10]  Rong JX, Qiu Y, Hansen MK, Zhu L, Zhang V, et al. (2007) Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone. Diabetes 56: 1751–1760.
[11]  Toseland CD, Campbell S, Francis I, Bugelski PJ, Mehdi N (2001) Comparison of adipose tissue changes following administration of rosiglitazone in the dog and rat. Diabetes Obes Metab 3: 163–170.
[12]  Bolten CW, Blanner PM, McDonald WG, Staten NR, Mazzarella RA, et al. (2007) Insulin sensitizing pharmacology of thiazolidinediones correlates with mitochondrial gene expression rather than activation of PPAR gamma. Gene Regul Syst Bio 1: 73–82.
[13]  Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, et al. (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310: 314–317.
[14]  Phielix E, Meex R, Moonen-Kornips E, Hesselink MK, Schrauwen P (2010) Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia 53: 1714–1721.
[15]  Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, et al. (2003) Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes 52: 1888–1896.
[16]  Rosen ED, Spiegelman BM (2001) PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276: 37731–37734.
[17]  Boden G, Homko C, Mozzoli M, Showe LC, Nichols C, et al. (2005) Thiazolidinediones upregulate fatty acid uptake and oxidation in adipose tissue of diabetic patients. Diabetes 54: 880–885.
[18]  Wilson-Fritch L, Nicoloro S, Chouinard M, Lazar MA, Chui PC, et al. (2004) Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest 114: 1281–1289.
[19]  Hock MB, Kralli A (2009) Transcriptional control of mitochondrial biogenesis and function. Annu Rev Physiol 71: 177–203.
[20]  Scarpulla RC (2008) Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiol Rev 88: 611–638.
[21]  Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1: 361–370.
[22]  Desautels M (1985) Mitochondrial thermogenin content is unchanged during atrophy of BAT of fasting mice. Am J Physiol 249: E99–106.
[23]  Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24: 78–90.
[24]  Hallakou S, Doare L, Foufelle F, Kergoat M, Guerre-Millo M, et al. (1997) Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 46: 1393–1399.
[25]  Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, et al. (1998) Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 101: 1354–1361.
[26]  Sears DD, Hsiao G, Hsiao A, Yu JG, Courtney CH, et al. (2009) Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization. Proc Natl Acad Sci U S A 106: 18745–18750.
[27]  Puigserver P, Wu Z, Park CW, Graves R, Wright M, et al. (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92: 829–839.
[28]  Tiraby C, Tavernier G, Lefort C, Larrouy D, Bouillaud F, et al. (2003) Acquirement of brown fat cell features by human white adipocytes. J Biol Chem 278: 33370–33376.
[29]  Valle I, Alvarez-Barrientos A, Arza E, Lamas S, Monsalve M (2005) PGC-1alpha regulates the mitochondrial antioxidant defense system in vascular endothelial cells. Cardiovasc Res 66: 562–573.
[30]  Handschin C, Choi CS, Chin S, Kim S, Kawamori D, et al. (2007) Abnormal glucose homeostasis in skeletal muscle-specific PGC-1alpha knockout mice reveals skeletal muscle-pancreatic beta cell crosstalk. J Clin Invest 117: 3463–3474.
[31]  Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, et al. (1992) Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci 103(Pt 4): 931–942.
[32]  Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G, et al. (2000) Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol 279: C670–681.
[33]  Orci L, Cook WS, Ravazzola M, Wang MY, Park BH, et al. (2004) Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci U S A 101: 2058–2063.
[34]  Sell H, Berger JP, Samson P, Castriota G, Lalonde J, et al. (2004) Peroxisome proliferator-activated receptor gamma agonism increases the capacity for sympathetically mediated thermogenesis in lean and ob/ob mice. Endocrinology 145: 3925–3934.
[35]  Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, et al. (2010) 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 285: 7153–7164.
[36]  Debevec D, Christian M, Morganstein D, Seth A, Herzog B, et al. (2007) Receptor interacting protein 140 regulates expression of uncoupling protein 1 in adipocytes through specific peroxisome proliferator activated receptor isoforms and estrogen-related receptor alpha. Mol Endocrinol 21: 1581–1592.
[37]  Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, et al. (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119: 121–135.
[38]  Uldry M, Yang W, St-Pierre J, Lin J, Seale P, et al. (2006) Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab 3: 333–341.
[39]  Kressler D, Schreiber SN, Knutti D, Kralli A (2002) The PGC-1-related protein PERC is a selective coactivator of estrogen receptor alpha. J Biol Chem 277: 13918–13925.
[40]  Lin J, Puigserver P, Donovan J, Tarr P, Spiegelman BM (2002) Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem 277: 1645–1648.
[41]  Kamei Y, Ohizumi H, Fujitani Y, Nemoto T, Tanaka T, et al. (2003) PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci U S A 100: 12378–12383.
[42]  St-Pierre J, Lin J, Krauss S, Tarr PT, Yang R, et al. (2003) Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells. J Biol Chem 278: 26597–26603.
[43]  Meirhaeghe A, Crowley V, Lenaghan C, Lelliott C, Green K, et al. (2003) Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo. Biochem J 373: 155–165.
[44]  Lelliott CJ, Medina-Gomez G, Petrovic N, Kis A, Feldmann HM, et al. (2006) Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol 4: e369.
[45]  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 U S A 104: 5223–5228.
[46]  Vianna CR, Huntgeburth M, Coppari R, Choi CS, Lin J, et al. (2006) Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance. Cell Metab 4: 453–464.
[47]  Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR, et al. (2005) PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3: e101.
[48]  Lai L, Leone TC, Zechner C, Schaeffer PJ, Kelly SM, et al. (2008) Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev 22: 1948–1961.
[49]  Andersson U, Scarpulla RC (2001) Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol Cell Biol 21: 3738–3749.
[50]  Vercauteren K, Gleyzer N, Scarpulla RC (2009) Short hairpin RNA-mediated silencing of PRC (PGC-1-related coactivator) results in a severe respiratory chain deficiency associated with the proliferation of aberrant mitochondria. J Biol Chem 284: 2307–2319.
[51]  Deng T, Sieglaff DH, Zhang A, Lyon CJ, Ayers SD, et al. (2011) A Peroxisome Proliferator-activated Receptor {gamma} (PPAR{gamma})/PPAR{gamma} Coactivator 1{beta} Autoregulatory Loop in Adipocyte Mitochondrial Function. J Biol Chem 286: 30723–30731.
[52]  Nedergaard J, Cannon B (2010) The changed metabolic world with human brown adipose tissue: therapeutic visions. Cell Metab 11: 268–272.
[53]  Guerra C, Koza RA, Yamashita H, Walsh K, Kozak LP (1998) Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest 102: 412–420.
[54]  Kopecky J, Clarke G, Enerback S, Spiegelman B, Kozak LP (1995) Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Invest 96: 2914–2923.
[55]  Kopecky J, Hodny Z, Rossmeisl M, Syrovy I, Kozak LP (1996) Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution. Am J Physiol 270: E768–775.
[56]  Feldmann HM, Golozoubova V, Cannon B, Nedergaard J (2009) UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 9: 203–209.
[57]  Summermatter S, Baum O, Santos G, Hoppeler H, Handschin C (2011) Peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha} (PGC-1{alpha}) promotes skeletal muscle lipid refueling in vivo by activating de novo lipogenesis and the pentose phosphate pathway. J Biol Chem 285: 32793–32800.
[58]  Espinoza DO, Boros LG, Crunkhorn S, Gami H, Patti ME (2010) Dual modulation of both lipid oxidation and synthesis by peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta in cultured myotubes. FASEB J 24: 1003–1014.
[59]  Lin J, Yang R, Tarr PT, Wu PH, Handschin C, et al. (2005) Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell 120: 261–273.
[60]  Luo J, Sladek R, Carrier J, Bader JA, Richard D, et al. (2003) Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol Cell Biol 23: 7947–7956.
[61]  Villena JA, Kralli A (2008) ERRalpha: a metabolic function for the oldest orphan. Trends Endocrinol Metab 19: 269–276.
[62]  Rodriguez CI, Buchholz F, Galloway J, Sequerra R, Kasper J, et al. (2000) High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP. Nat Genet 25: 139–140.
[63]  Villena JA, Roy S, Sarkadi-Nagy E, Kim KH, Sul HS (2004) Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. J Biol Chem 279: 47066–47075.
[64]  Villena JA, Hock MB, Chang WY, Barcas JE, Giguere V, et al. (2007) Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis. Proc Natl Acad Sci U S A 104: 1418–1423.
[65]  Srere PA (1969) Citrate synthase. Methos in enzymology 13: 3–11.
[66]  Pallotti F, Lenaz G (2001) Isolation and subfractionation of mitochondria from animal cells and tissue culture cell lines. In: Pon LA, Schon EA, editors. Mitochondria. 2001 ed. San Diego: Academic Press. pp. 1–35.
[67]  Degli M (2001) Assessing functional integrity of mitochondria in vitro and in vivo. In: Pon LA, Schon EA, editors. Mitochindria. ed. San Diego: Academic Press. pp. 75–96.


comments powered by Disqus

Contact Us


微信:OALib Journal