International Journal of Obesity (2005) 29, S3–S4 & 2005 Nature Publishing Group All rights reserved 0307-0565/05 $30.00 www.nature.com/ijo PAPER Role of PPARc, transcriptional cofactors, and adiponectin in the regulation of nutrient metabolism, adipogenesis and insulin action: view from the chair

JP Berger1*

1Department of Metabolic Disorders, Merck Research Laboratories, Rahway, NJ, USA

International Journal of Obesity (2005) 29, S3–S4. doi:10.1038/sj.ijo.0802904

The peroxisome proliferator-activated receptors (PPARs) PPARg coactivator-1 (PGC-1), a transcriptional coactivator compose a nuclear receptor subfamily.1 The three PPAR that was first identified as a result of its high affinity for the isoforms, g, a and d, which are encoded by three separate receptor from which it takes its name, was discussed by Pere genes, are nutrient sensors that regulate metabolic homeo- Puigserver. Only by interacting with PGC-1 and activating the stasis. They are ligand-regulated transcription factors whose transcription of mitochondrial UCP-1 can PPARg induce main physiological actions are mediated by altering gene brown adipocyte differentiation.3 To induce the expression expression. PPARs heterodimerize with RXR, then bind to of all the genes required for a complete thermogenic response peroxisome proliferator response elements in regulatory in brown adipocytes, PGC-1 also serves as a coactivator of domains of genes. Upon being bound by agonists, PPAR other nuclear receptors including PPARa, TR, RAR and ERRa. conformation is changed such that it binds with high Additionally, when thermogenesis is required, PGC-1 is affinity to coactivators that remodel chromatin and com- upregulated and stabilized by the sympathetic nervous system municate with the cellular transcriptional machinery. As a via activation of b-adrenoreceptor transduction pathways. result, transcriptional initiation is induced and the levels of PGC-1 also plays a critical role in the differentiation and PPAR-responsive transcripts increase. metabolic activity of skeletal muscle, a major site of energy PPARg is highly expressed in adipose tissue. Activation of utilization during exercise.4 The coactivator is sufficient for PPARg induces adipocyte differentiation and lipid accumula- the induction of mitochondria biogenesis and the genera- tion by adipocytes by modulating numerous genes regu- tion of type 1 (slow twitch) muscle. Calcium signaling lating adipogenesis, lipid uptake and lipid metabolism. cascades elevate PGC-1 muscle expression by activating Notably, PPARg null cells cannot differentiate into adipocytes transcription factors that have response elements in the and the adipose-specific ablation of PPARg results in coactivator’s promoter. Pharmacological activation of PGC-1 adipocyte hypocellularity and reduced adiposity. Thiazolidi- in muscle might mitigate obesity. nedione (TZD) insulin-sensitizing agents are PPARg ligands; PGC-1 not only induces lipid catabolism but also hepatic their antidiabetic efficacy in vivo has been shown to correlate gluconeogenesis during the fasted and diabetic states.5 with their receptor agonist potency. The insulin-sensitizing Glucagon increases PGC-1 expression by cAMP-dependent action of PPARg agonists results from their ability to lower transduction pathways that synergize with glucocorticoid circulating free fatty acids by decreasing adipocyte lipolysis, signaling cascades; the coactivator then interacts with several regulate the expression of proteins that modulate insulin transcription factors to augment expression of key gluconeo- action and serve as adipose remodeling agents that direct genic enzymes. Inhibition of PGC-1-activated hepatic glucose lipids away from lipolytic visceral fat depots and into production may serve as treatment for diabetic hyperglycemia. subcutaneous fat tissue containing small, insulin-responsive Several important interactions between transcription fac- adipocytes.2 tors and signaling pathways that regulate the complex process of adipogenesis were detailed by Stephen Farmer. C/EBPb and C/EBPd cooperate with glucocorticoids to induce expression of PPARg, which in turn is necessary for C/EBPa *Correspondence: Dr JP Berger, Merck Research Laboratories, RY80N- 6 C31, PO Box 2000, 126 East Lincoln Avenue, Rahway, NJ 07065, USA. expression. These latter two transcription factors are E-mail: [email protected] required for terminal adipocyte differentiation. C/EBPb also Regulation of metabolism, adipogenesis and insulin action JP Berger S4 appears, in concert with a cAMP-dependent pathway, to PPARg, the research described clearly has evolved well promote the production of endogenous PPARg agonists by an beyond the characterization of that single molecule. It is as yet unknown cellular process.7 Furthermore, ERK/GSK3- the hope of this chairperson that such work will continue mediated phosphorylation of C/EBPb is necessary for PPARg unabated, not only to embellish our understanding of induction of the expression of C/EBPa and a subset of its important areas of biology but also to provide us with target genes, including the important adipocyte-secreted additional direction in the search for evermore efficacious protein adiponectin. b-Catenin, an element in the Wnt therapies for metabolic disease. signaling pathway, is targeted for proteosomal degradation when phosphorylated by GSK3b.PPARg activation promotes this process, which appears to positively affect PPARg target gene expression and adipogenesis.8 References Several atypical transcription factors that regulate PPARg 1 Berger J, Moller DE. The mechanism of action of PPARs. Ann Rev transcription during the transition between preadipocyte Med 2002; 53: 409–435. proliferation and adipocyte differentiation, commonly 2 Laplante M, Sell H, MacNaul KL, Richard D, Berger JP, Deshaies Y. PPAR-gamma activation mediates adipose depot-specific effects known as the clonal expansion phase, were described by on gene expression and lipoprotein lipase activity: mechanisms Lluis Fajas. E2F proteins are known to be important for modulation of postprandial lipemia and differential adipose regulators of the cell cycle. E2F1 directly activates PPARg accretion. Diabetes 2003; 52: 291–299. expression during clonal expansion of preadipocytes, while 3 Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to E2F4 directly represses transcription of the receptor during adaptive thermogenesis. Cell 1998; 92: 829–839. terminal adipocyte differentiation.9 E2F null mice display 4 Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, reduced adiposity, while those with diminished levels of Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, E2F4 are characterized by increased adipogenic potential. Spiegelman BM. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 2002; 418: The retinoblastoma protein RB has been show to play a role 797–801. in adipogenesis. Notably, PPARg induces adipocyte differ- 5 Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, entiation more robustly in the absence of RB because Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM. Control of hepatic gluconeogenesis through the formation of PPARg-RB-HDAC3 complexes represses the transcriptional coactivator PGC-1. Nature 2001; 413: 131–138. nuclear receptor’s ability to drive gene expression and 6 Wu Z, Bucher NL, Farmer SR. Induction of peroxisome prolif- adipogenesis.10 Conversely, dissociation of this receptor– erator-activated receptor gamma during the conversion of 3T3 cofactor heterotrimer stimulates adipocyte differentiation. fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol Cell Biol 1996; 16: 4128–4136. In addition to serving as a lipid reservoir, adipose tissue is 7 Hamm JK, Park BH, Farmer SR. A role for C/EBPbeta in regulating also an endocrine organ that mediates numerous physiolo- peroxisome proliferator-activated receptor gamma activity during gical events via the secretion of adipokines. PPARg regulates adipogenesis in 3T3-L1 preadipocytes. J Biol Chem 2001; 276: the expression of several adipocyte-secreted proteins includ- 18464–18471. 8 Moldes M, Zuo Y, Morrison RF, Silva D, Park BH, Liu J, Farmer SR. ing adiponectin, the biology of which was described by Peroxisome-proliferator-activated receptor gamma suppresses Philipp Scherer. Adiponectin is a 30 kDa protein containing a Wnt/beta-catenin signalling during adipogenesis. Biochem J 2003; short central collagenous region and a C-terminal TNFa-like 376: 607–613. domain.11 It circulates as both a hexamer and a high 9 Fajas L, Landsberg RL, Huss-Garcia Y, Sardet C, Lees JA, Auwerx J. E2Fs regulate adipocyte differentiation. Dev Cell 2002; 3: 39–49. molecular weight (HMW) oligomer. Adiponectin levels are 10 Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K, Debril MB, reduced in obese insulin-resistant subjects and type 2 Miard S, Auwerx J. The retinoblastoma-histone deacetylase diabetics. Importantly, adiponectin potentiates insulin in- 3 complex inhibits PPARgamma and adipocyte differentiation. hibition of hepatic gluconeogenesis.12 This insulin-sensitiz- Dev Cell 2002; 3: 903–910. 11 Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an ing activity appears to involve the activation of AMPK.13 adipokine regulating glucose and lipid metabolism. Trends Adiponectin may mediate the hepatic insulin-sensitizing Endocrinol Metab 2002; 13: 84–89. actions of TZDs. Transgenic mice overexpressing the protein 12 Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The display improved glucose tolerance and increased fat accretion, adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001; 7: 947–953. characteristics seen with TZD therapy. Furthermore, treatment 13 Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, of type 2 diabetics with TZDs elevates HMW adiponectin levels Nawrocki AR, Rajala MW, Parlow AF, Cheeseboro L, Ding YY, in a manner that correlates with their hepatic insulin- Russell RG, Lindemann D, Hartley A, Baker GR, Obici S, Deshaies sensitizing efficacy.14 Such data support the use of adiponectin Y, Ludgate M, Rossetti L, Scherer PE. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays as an early biomarker of PPARg agonist antidiabetic activity. elevated circulating adiponectin and improved insulin sensiti- In sum, the speakers in these symposium sessions vity. Endocrinology 2004; 145: 367–383. described numerous molecular elements that control nu- 14 Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger trient metabolism, energy homeostasis, adipogenesis and JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE. Complex insulin signaling. While a central, unifying theme of the distribution, not absolute amount of adiponectin, correlates with presentations was the important role played by the master thiazolidinedione-mediated improvement in insulin sensitivity. transcriptional regulator of adipocyte gene expression, J Biol Chem 2004; 279: 12152–12162.

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