Peroxisome proliferator-activated receptor gamma modulation and lipogenic response in adipocytes of small-for-gestational age offspring

Nutrition & Metabolism

Mina Desai²  Juan Vega³  Guang Han²  Robert H Lane¹  Michael G Ross²  Wai-Nang Paul Lee³  Jennifer K Yee³ 

[1] Division of Neonatology, University of Utah School of Medicine, Williams Building, P.O. Box 581289, Salt Lake City, UT 84158, USA;Department of Obstetrics and Gynecology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1000 West Carson Street, Harbor Box 446, Torrance, CA 90509, USA;Department of Pediatrics, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1000 West Carson Street, Harbor Box 446, Torrance, CA 90509, USA

关键词: Adipogenesis;    Fatty acid;    Stable isotope;    PPARγ;    Rosiglitazone;    Small-for-gestational age;    Adipocyte;   

Others  :  815244
DOI  :  10.1186/1743-7075-9-62

 received in 2012-04-12, accepted in 2012-06-14,  发布年份 2012

【 摘 要 】

Background

Small-for-gestational age (SGA) at birth increases risk of development of adult obesity and insulin resistance. A model of SGA rat offspring has been shown to exhibit increased adipose tissue expression of a key adipogenic transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), and increased fatty acid de novo synthesis during the nursing period, prior to onset of obesity. PPARγ agonists have been studied for potential use in the prevention of insulin resistance. Moreover, SGA adipocytes exhibit age-dependent differences in lipogenesis as mediated by PPARγ. The effects of PPARγ modulators on lipogenic gene expression and de novo lipogenesis on the age-dependent changes in SGA adipocytes are not known. The objectives of this study were: 1) to determine the adipogenic and lipogenic potential in SGA adipocytes at postnatal day 1 (p1) and day 21 (p21), 2) to determine how the PPARγ activator- and repressor-ligands affect the lipogenic potential, and 3) to determine the fatty acid metabolic response to PPARγ activator-ligand treatment.

Methods

Primary adipocyte cultures from p1 and p21 SGA and Control male offspring were established from a known maternal food-restriction model of SGA. Cell proliferation and Oil Red O (ORO) staining were quantified. Adipocytes were treated with increasing doses of rosiglitazone or bisphenol-A diglycidyl ether (BADGE). PPARγ and SREBP1 protein expression were determined. De novo lipogenesis with rosiglitazone treatment at p21 was studied using 50% U¹³C-glucose and gas chromatography/mass spectrometry.

Results

At p1 and p21, SGA demonstrated increased cell proliferation and increased ORO staining. At p21, SGA demonstrated increased lipogenic gene expression and increased glucose-mediated fatty acid de novo synthesis compared with Controls. In response to rosiglitazone, SGA adipocytes further increased glucose utilization for fatty acid synthesis. SGA lipogenic gene expression demonstrated resistance to BADGE treatment.

Conclusions

SGA adipocytes exhibit an enhanced adipogenic and lipogenic potential in early postnatal life. By p21, SGA demonstrated resistance to PPARγ repressor-ligand treatment, and selective response to high dose PPARγ activator-ligand treatment in adipogenic and lipogenic gene expression. p21 SGA adipocytes revealed increased fatty acid de novo synthesis through a complex relationship with glucose metabolism.

【 授权许可】

   
2012 Yee et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, Bleker OP: Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 1999, 70:811-816.
• [2]Ravelli GP, Stein ZA, Susser MW: Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976, 295:349-353.
• [3]Yee JK, Lee WN, Han G, Ross MG, Desai M: Organ-specific alterations in fatty acid de novo synthesis and desaturation in a rat model of programmed obesity. Lipids Health Dis 2011, 10:72.
• [4]Desai M, Gayle D, Babu J, Ross MG: Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol 2005, 288:R91-R96.
• [5]Desai M, Gayle D, Babu J, Ross MG: The timing of nutrient restriction during rat pregnancy/lactation alters metabolic syndrome phenotype. Am J Obstet Gynecol 2007, 196:e551-e557.
• [6]Desai M, Gayle D, Han G, Ross MG: Programmed hyperphagia due to reduced anorexigenic mechanisms in intrauterine growth-restricted offspring. Reprod Sci 2007, 14:329-337.
• [7]Desai M, Guang H, Ferelli M, Kallichanda N, Lane RH: Programmed upregulation of adipogenic transcription factors in intrauterine growth-restricted offspring. Reprod Sci 2008, 15:785-796.
• [8]Kim JB, Spiegelman BM: ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 1996, 10:1096-1107.
• [9]Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006, 355:2427-2443.
• [10]Albrektsen T, Frederiksen KS, Holmes WE, Boel E, Taylor K, Fleckner J: Novel genes regulated by the insulin sensitizer rosiglitazone during adipocyte differentiation. Diabetes 2002, 51:1042-1051.
• [11]Muhlhausler BS, Morrison JL, McMillen IC: Rosiglitazone increases the expression of peroxisome proliferator-activated receptor-gamma target genes in adipose tissue, liver, and skeletal muscle in the sheep fetus in late gestation. Endocrinology 2009, 150:4287-4294.
• [12]Kim SK, Park CK, Lee SY, Song JS, Park SH, Kim YK: Effects of Rosiglitazone on the Expression of PPAR-gamma and the Production of IL-6 and IL-8 in Acute Lung Injury Model Using Human Pulmonary Epithelial Cells. Trop J Pharm Res 2011, 10:559-566.
• [13]Johnson JA, Trasino SE, Ferrante AW, Vasselli JR: Prolonged decrease of adipocyte size after rosiglitazone treatment in high- and low-fat-fed rats. Obesity (Silver Spring) 2007, 15:2653-2663.
• [14]Ye JM, Dzamko N, Cleasby ME, Hegarty BD, Furler SM, Cooney GJ, Kraegen EW: Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin. Diabetologia 2004, 47:1306-1313.
• [15]Oakes ND, Thalen PG, Jacinto SM, Ljung B: Thiazolidinediones increase plasma-adipose tissue FFA exchange capacity and enhance insulin-mediated control of systemic FFA availability. Diabetes 2001, 50:1158-1165.
• [16]Wright HM, Clish CB, Mikami T, Hauser S, Yanagi K, Hiramatsu R, Serhan CN, Spiegelman BM: A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem 2000, 275:1873-1877.
• [17]Kota BP, Huang TH, Roufogalis BD: An overview on biological mechanisms of PPARs. Pharmacol Res 2005, 51:85-94.
• [18]Lowenstein JM, Brunengraber H, Wadke M: Measurement of rates of lipogenesis with deuterated and tritiated water. Methods Enzymol 1975, 35:279-287.
• [19]Lee WN, Byerley LO, Bergner EA, Edmond J: Mass isotopomer analysis: theoretical and practical considerations. Biol Mass Spectrom 1991, 20:451-458.
• [20]Yee JK, Mao CS, Hummel HS, Lim S, Sugano S, Rehan VK, Xiao G, Lee WN: Compartmentalization of stearoyl-coenzyme A desaturase 1 activity in HepG2 cells. J Lipid Res 2008, 49:2124-2134.
• [21]Lee WN, Edmond J, Bassilian S, Morrow JW: Mass isotopomer study of glutamine oxidation and synthesis in primary culture of astrocytes. Dev Neurosci 1996, 18:469-477.
• [22]Des Rosiers C, Lloyd S, Comte B, Chatham JC: A critical perspective of the use of (13)C-isotopomer analysis by GCMS and NMR as applied to cardiac metabolism. Metab Eng 2004, 6:44-58.
• [23]Bartnik BL, Hovda DA, Lee PW: Glucose metabolism after traumatic brain injury: estimation of pyruvate carboxylase and pyruvate dehydrogenase flux by mass isotopomer analysis. J Neurotrauma 2007, 24:181-194.
• [24]Kirkland JL, Hollenberg CH, Gillon WS: Age, anatomic site, and the replication and differentiation of adipocyte precursors. Am J Physiol 1990, 258:C206-C210.
• [25]Honma T, Yanaka M, Tsuduki T, Ikeda I: Increased lipid accumulation in liver and white adipose tissue in aging in the SAMP10 mouse. J Nutr Sci Vitaminol (Tokyo) 2011, 57:123-129.
• [26]Ibanez L, Lopez-Bermejo A, Suarez L, Marcos MV, Diaz M, de Zegher F: Visceral adiposity without overweight in children born small for gestational age. J Clin Endocrinol Metab 2008, 93:2079-2083.
• [27]Yki-Jarvinen H: Thiazolidinediones. N Engl J Med 2004, 351:1106-1118.
• [28]Collins JM, Neville MJ, Pinnick KE, Hodson L, Ruyter B, van Dijk TH, Reijngoud DJ, Fielding MD, Frayn KN: De novo lipogenesis in the differentiating human adipocyte can provide all fatty acids necessary for maturation. J Lipid Res 2011, 52:1683-1692.
• [29]Gluckman PD, Hanson MA: Living with the past: evolution, development, and patterns of disease. Science 2004, 305:1733-1736.
• [30]Hevener AL, Reichart D, Janez A, Olefsky J: Thiazolidinedione treatment prevents free fatty acid-induced insulin resistance in male wistar rats. Diabetes 2001, 50:2316-2322.
• [31]Chung SS, Kim M, Youn BS, Lee NS, Park JW, Lee IK, Lee YS, Kim JB, Cho YM, Lee HK, Park KS: Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor gamma in human skeletal muscle cells. Mol Cell Biol 2009, 29:20-30.