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Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor γ (PPARγ) and PPARγcoactivator-1 (PGC1)

  • Gema Medina-Gomez (a1), Sarah Gray (a1) and Antonio Vidal-Puig (a1)
Abstract

Obesity is characterised by an increase in the adipose deposits, resulting from an imbalance between food intake and energy expenditure. When expansion of the adipose tissue reaches its maximum limit, as in obesity, fat accumulates in non-adipose tissues such as liver, heart, muscle and pancreas, developing a toxic response known as lipotoxicity, a condition that promotes the development of insulin resistance and other metabolic complications. Thus, the lipotoxic state may contribute to the increased risk of insulin resistance, diabetes, fatty liver and cardiovascular complications associated with obesity.

We are interested in studying adipose tissue, specifically how mechanisms of adipogenesis and remodelling of adipose tissue, in terms of size and function of the adipocytes, could be considered a strategy to increase the capacity for lipid storage and prevent lipotoxicity. The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors that regulate energy balance by promoting either energy deposition or energy dissipation. Under normal physiological conditions, PPARγ is mainly expressed in adipose tissue and regulates diverse functions such as the development of fat cells and their capacity to store lipids. The generation of PPARγ knockout mice, either tissue specific or isoform specific, has provided new models to study PPARγ’s role in adipose tissue differentiation and function and have highlighted the essential role of PPARγ in adipogenesis and lipogenesis.

A second strategy to prevent lipotoxicity is to increase the capacity of tissues to oxidise fatty acids. PPARγcoactivator-1α is a coactivator of PPARγ that induces the expression of genes that promote the differentiation of preadipocytes to brown adipocytes. Recently, it has been implicated in increasing the oxidation of fatty acids via increasing mitochondrial capacity and function, making this co-factor a key candidate for the treatment of lipotoxicity.

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Corresponding author: Email mgm28@cam.ac.uk
References
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1Medina-Gomez, G, Virtue, S, Lelliott, C, Boiani, R, Campbell, M, Christodoulides, C, et al. . The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-gamma2 isoform. Diabetes 2005; 54: 17061716.
2Rosen, ED, Spiegelman, BM. Molecular regulation of adipogenesis. Annual Review of Cell Developmental Biology 2000; 16: 145171.
3Dandona, P, Aljada, A, Bandyopadhyay, A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends in Immunology 2004; 25: 47.
4Wellen, KE, Hotamisligil, GS. Inflammation, stress, and diabetes. Journal of Clinical Investigation 2005; 115: 11111119.
5Kraegen, EW, Cooney, GJ, Ye, JM, Thompson, AL, Furler, SM. The role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type II diabetes and obesity. Experimental and Clinical Endocrinology and Diabetes 2001; 109 (Suppl. 2): S189S201.
6Lelliott, C, Vidal-Puif, AJ. Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. International Journal of Obesity and Related Metabolic Disorders 2004; 28 (Suppl. 4): S22S28.
7McGarry, JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 2002; 51: 718.
8Unger, RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology 2003; 144: 51595165.
9Zhang, Y, Proenca, R, Maffei, M, Barone, M, Leopold, L, Friedman, JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425432.
10Saltiel, AR. You are what you secrete. Nature Medicine 2001; 7: 887888.
11Fruhbeck, G, Gomez-Ambrosi, J, Muruzabal, FJ, Burrell, MA. The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. American Journal of Physiology Endocrinology and Metabolism 2001; 280: E827E847.
12Farooqi, IS, Jebb, SA, Langmack, G, Lawrence, E, Cheetham, CH, Prentice, AM, et al. . Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New England Journal of Medicine 1999; 341: 879884.
13Montague, CT, Farooqi, IS, Whitehead, JP, Soos, MA, Rau, H, Wareham, NJ, et al. . Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903908.
14Shimomura, I, Hammer, RE, Ikemoto, S, Brown, MS, Goldstein, JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999; 401: 7376.
15Kubota, N, Terauchi, Y, Yamauchi, T, Kubota, T, Moroi, M, Matsui, J, et al. . Disruption of adiponectin causes insulin resistance and neointimal formation. Journal of Biological Chemistry 2002; 277: 2586325866.
16Stumvoll, M, Tschritter, O, Fritsche, A, Staiger, H, Renn, W, Weisser, M, et al. . Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity: interaction with family history of type 2 diabetes. Diabetes 2002; 51: 3741.
17Rajala, MW, Scherer, PE. Minireview: The adipocyte – at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 2003; 144: 37653773.
18Steppan, CM, Bailey, ST, Bhat, S, Brown, EJ, Banerjee, RR, Wright, CM, et al. . The hormone resistin links obesity to diabetes. Nature 2001; 409: 307312.
19Unger, RH, Orci, L. Lipoapoptosis: its mechanism and its diseases. Biochimica et Biophysica Acta 2002; 1585: 202212.
20Shulman, GI. Cellular mechanisms of insulin resistance. Journal of Clinical Investigation 2000; 106: 171176.
21Russell, AP. Lipotoxicity: the obese and endurance-trained paradox. International Journal of Obesity and Related Metabolic Disorders 2004; 28 (Suppl. 4): S66S71.
22Manco, M, Calvani, M, Mingrone, G. Effects of dietary fatty acids on insulin sensitivity and secretion. Diabetes, Obesity and Metabolism 2004; 6: 402413.
23Unger, RH. Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie 2005; 87: 5764.
24Unger, RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 1995; 44: 863870.
25Shimabukuro, M, Wang, MY, Zhou, YT, Newgard, CB, Unger, RH. Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. Proceedings of the National Academy of Sciences of the United States of America 1998; 95: 95589561.
26Barak, Y, Nelson, MC, Ong, ES, Jones, YZ, Ruiz-Lozano, P, Chien, KR, et al. . PPAR gamma is required for placental, cardiac, and adipose tissue development. Molecular Cell 1999; 4: 585595.
27Rosen, ED, Sarraf, P, Troy, AE, Bradwin, G, Moore, K, Milstone, DS, et al. . PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Molecular Cell 1999; 4: 611617.
28Spiegelman, BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47: 507514.
29Miles, PD, Barak, Y, Evans, RM, Olefsky, JM. Effect of heterozygous PPARgamma deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding. American Journal of Physiology Endocrinology and Metabolism 2003; 284: E618E626.
30Tonelli, J, Li, W, Kishore, P, Pajvani, UB, Kwon, E, Weaver, C, et al. . Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes 2004; 53: 16211629.
31Sugiyama, Y, Murase, K, Ikeda, H. [Mechanisms of thiazolidinedione derivatives for hypoglycemic and insulin sensitizing effects]. Nippon Rinsho 2000; 58: 370375.
32Hauner, H. The mode of action of thiazolidinediones. Diabetes/Metabolism Research and Reviews 2002; 18 (Suppl. 2): S10S15.
33Koutnikova, H, Cock, TA, Watanabe, M, Houten, SM, Champy, MF, Dierich, A, et al. . Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice. Proceedings of the National Academy of Sciences of the United States of America 2003; 100: 1445714462.
34He, W, Barak, Y, Hevener, A, Olson, P, Liao, D, Le, J, et al. . Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proceedings of the National Academy of Sciences of the United States of America 2003; 100: 1571215717.
35Molina, JM, Ciaraldi, TP, Brady, D, Olefsky, JM. Decreased activation rate of insulin-stimulated glucose transport in adipocytes from obese subjects. Diabetes 1989; 38: 991995.
36Olefsky, JM. Mechanisms of decreased insulin responsiveness of large adipocytes. Endocrinology 1977; 100: 11691177.
37Weyer, C, Foley, JE, Bogardus, C, Tataranni, PA, Pratley, RE. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 2000; 43: 14981506.
38Miles, PD, Barak, Y, He, W, Evans, RM, Olefsky, JM. Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. Journal of Clinical Investigation 2000; 105: 287292.
39Yamauchi, T, Kamon, J, Waki, H, Murakami, K, Motojima, K, Komeda, K, et al. . The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. Journal of Biological Chemistry 2001; 276: 4124541254.
40Escher, P, Braissant, O, Basu-Modak, S, Michalik, L, Wahli, W, Desvergne, B. Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology 2001; 142: 41954202.
41Werman, A, Hollenberg, A, Solanes, G, Bjorbaek, C, Vidal-Puig, AJ, Flier, JS. Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin. Journal of Biological Chemistry 1997; 272: 2023020235.
42Ren, D, Collingwood, TN, Rebar, EJ, Wolffe, AP, Camp, HS. PPARgamma knockdown by engineered transcription factors: exogenous PPARgamma2 but not PPARgamma1 reactivates adipogenesis. Genes and Development 2002; 16: 2732.
43Vidal-Puig, A, Jimenez-Linan, M, Lowell, BB, Hamann, A, Hu, E, Spiegelman, B, et al. . Regulation of PPAR gamma gene expression by nutrition and obesity in rodents. Journal of Clinical Investigation 1996; 97: 25532561.
44Vidal-Puig, AJ, Considine, RV, Jimenez-Linan, M, Werman, A, Pories, WJ, Caro, JF, et al. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. Journal of Clinical Investigation 1997; 99: 24162422.
45Uno, K, Katagiri, H, Yamada, T, Ishigaki, Y, Ogihara, T, Imai, J, et al. . Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. Science 2006; 312: 16561659.
46Zhang, J, Fu, M, Cui, T, Xiong, C, Xu, K, Zhong, W, et al. . Selective disruption of PPAR{gamma}2 impairs the development of adipose tissue and insulin sensitivity. Proceedings of the National Academy of Sciences of the United States of America 2004; 101: 1070310708.
47Puigserver, P, Wu, Z, Park, CW, Graves, R, Wright, M, Spiegelman, BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998; 92: 829839.
48Herzig, S, Long, F, Jhala, US, Hedrick, S, Quinn, R, Bauer, A, et al. . CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 2001; 413: 179183.
49Rhee, J, Inoue, Y, Yoon, JC, Puigserver, P, Fan, M, Gonzalez, FJ, et al. . Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proceedings of the National Academy of Sciences of the United States of America 2003; 100: 40124017.
50Yoon, JC, Puigserver, P, Chen, G, Donovan, J, Wu, Z, Rhee, J, et al. . Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 2001; 413: 131138.
51Michael, LF, Wu, Z, Cheatham, RB, Puigserver, P, Adelmant, G, Lehman, JJ, et al. . Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proceedings of the National Academy of Sciences of the United States of America 2001; 98: 38203825.
52Lin, J, Wu, H, Tarr, PT, Zhang, CY, Wu, Z, Boss, O, et al. . Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 2002; 418: 797801.
53Lin, J, Tarr, PT, Yang, R, Rhee, J, Puigserver, P, Newgard, CB, et al. . PGC-1beta in the regulation of hepatic glucose and energy metabolism. Journal of Biological Chemistry 2003; 278: 3084330848.
54Tiraby, C, Tavernier, G, Lefort, C, Larrouy, D, Bouillaud, F, Ricquier, D, et al. . Acquirement of brown fat cell features by human white adipocytes. Journal of Biological Chemistry 2003; 278: 3337033376.
55Meirhaeghe, A, Crowley, V, Lenaghan, C, Lelliott, C, Green, K, Stewart, A, et al. . Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo. Biochemical Journal 2003; 373: 155165.
56Lin, J, Puigserver, P, Donovan, J, Tarr, P, Spiegelman, BM. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor. Journal of Biological Chemistry 2002; 277: 16451648.
57Mortensen, OH, Frandsen, L, Schjerling, P, Nishimura, E, Grunnet, N. PGC-1{alpha} and PGC-1{beta} have both similar and distinct effects upon myofiber switching towards an oxidative phenotype. American Journal of Physiology Endocrinology and Metabolism 2006; 291: E807E816.
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