Intrauterine growth restriction (IUGR) predisposes to obesity and adipose dysfunction. We previously demonstrated IUGR-induced increased visceral adipose deposition and dysregulated expression of peroxisome proliferator activated receptor-γ2 (PPARγ2) in male adolescent rats, prior to the onset of obesity. In other studies, activation of PPARγ increases subcutaneous adiponectin expression and normalizes visceral adipose deposition. We hypothesized that maternal supplementation with docosahexaenoic acid (DHA), a PPARγ agonist, would normalize IUGR adipose deposition in association with increased PPARγ, adiponectin, and adiponectin receptor expression in subcutaneous adipose. To test these hypotheses, we used a well-characterized model of uteroplacental-insufficiency-(UPI-) induced IUGR in the rat with maternal DHA supplementation. Our primary findings were that maternal DHA supplementation during rat pregnancy and lactation (1) normalizes IUGR-induced changes in adipose deposition and visceral PPARγ expression in male rats and (2) increases serum adiponectin, as well as adipose expression of adiponectin and adiponectin receptors in former IUGR rats. Our novel findings suggest that maternal DHA supplementation may normalize adipose dysfunction and promote adiponectin-induced improvements in metabolic function in IUGR. 1. Introduction Intrauterine growth restriction (IUGR) predisposes to adult onset disease. The development of obesity following IUGR is well documented and results from adipose dysfunction [1–3]. While IUGR infants are smaller than their appropriately grown counterparts at birth, their rate of weight accretion is accelerated in childhood and they acquire more adipose tissue. An important concept is that IUGR adipose tissue is dysregulated before the onset of obesity [4, 5]. In addition to increased relative amounts of adipose tissue, adipose deposition in IUGR children favors formation of visceral adipose tissue (VAT) over subcutaneous adipose tissue (SAT) [6–8]. We previously demonstrated that IUGR increases the ratio of VAT to SAT in male adolescent rats, prior to the onset of obesity, with no effect in female rats [9]. The changes in adipose deposition in IUGR were accompanied by increased expression of the adipogenic transcription factor peroxisome proliferator activated receptor-γ2 (PPARγ2) in VAT, but not SAT, of male rats [9]. An important transcriptional target of PPARγ is adiponectin [10, 11]. Adiponectin improves insulin sensitivity and normalizes adipose deposition [12]. When mice with excessive VAT deposition overexpress
References
[1]
M. G. Ross and M. H. Beall, “Adult Sequelae of Intrauterine Growth Restriction,” Seminars in Perinatology, vol. 32, no. 3, pp. 213–218, 2008.
[2]
E. C. Cottrell and S. E. Ozanne, “Early life programming of obesity and metabolic disease,” Physiology and Behavior, vol. 94, no. 1, pp. 17–28, 2008.
[3]
J. C. K. Wells, S. Chomtho, and M. S. Fewtrell, “Programming of body composition by early growth and nutrition,” Proceedings of the Nutrition Society, vol. 66, no. 3, pp. 423–434, 2007.
[4]
S. Chakraborty, D. V. Joseph, M. J. G. Bankart, S. A. Petersen, and M. P. Wailoo, “Fetal growth restriction: relation to growth and obesity at the age of 9 years,” Archives of Disease in Childhood, vol. 92, no. 6, pp. F479–F483, 2007.
[5]
D. Jaquet, S. Deghmoun, D. Chevenne, D. Collin, P. Czernichow, and C. Lévy-Marchal, “Dynamic change in adiposity from fetal to postnatal life is involved in the metabolic syndrome associated with reduced fetal growth,” Diabetologia, vol. 48, no. 5, pp. 849–855, 2005.
[6]
E. L. Rasmussen, C. Malis, C. B. Jensen et al., “Altered fat tissue distribution in young adult men who had low birth weight,” Diabetes Care, vol. 28, no. 1, pp. 151–153, 2005.
[7]
L. Ibá？ez, A. Lopez-Bermejo, L. Suárez, M. V. Marcos, M. Díaz, and F. De Zegher, “Visceral adiposity without overweight in children born small for gestational age,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 6, pp. 2079–2083, 2008.
[8]
C. S. Yajnik, H. G. Lubree, S. S. Rege et al., “Adiposity and hyperinsulinemia in Indians are present at birth,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 12, pp. 5575–5580, 2002.
[9]
L. A. Joss-Moore, Y. Wang, M. S. Campbell et al., “Uteroplacental insufficiency increases visceral adiposity and visceral adipose PPARγ2 expression in male rat offspring prior to the onset of obesity,” Early Human Development, vol. 86, no. 3, pp. 179–185, 2010.
[10]
A. Banga, R. Unal, P. Tripathi et al., “Adiponectin translation is increased by the PPARγ agonists pioglitazone and ω-3 fatty acids,” American Journal of Physiology, vol. 296, no. 3, pp. E480–E489, 2009.
[11]
G. Krey, O. Braissant, F. L'Horset et al., “Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay,” Molecular Endocrinology, vol. 11, no. 6, pp. 779–791, 1997.
[12]
J. Kim, E. Van De Wall, M. Laplante et al., “Obesity-associated improvements in metabolic profile through expansion of adipose tissue,” Journal of Clinical Investigation, vol. 117, no. 9, pp. 2621–2637, 2007.
[13]
P. R. Devchand, A. Ijpenberg, B. Devesvergne, and W. Wahli, “PPARs: nuclear receptors for fatty acids, eicosanoids, and xenobiotics,” Advances in Experimental Medicine and Biology, vol. 469, pp. 231–236, 2000.
[14]
P. Flachs, O. Horakova, P. Brauner et al., “Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce β-oxidation in white fat,” Diabetologia, vol. 48, no. 11, pp. 2365–2375, 2005.
[15]
C. Stryjecki and D. M. Mutch, “Fatty acid-gene interactions, adipokines and obesity,” European Journal of Clinical Nutrition, vol. 65, no. 3, pp. 285–297, 2011.
[16]
T. Kadowaki and T. Yamauchi, “Adiponectin and adiponectin receptors,” Endocrine Reviews, vol. 26, no. 3, pp. 439–451, 2005.
[17]
R. H. Lane, A. E. Tsirka, and E. M. Gruetzmacher, “Uteroplacental insufficiency alters cerebral mitochondrial gene expression and DNA in fetal and juvenile rats,” Pediatric Research, vol. 47, no. 6, pp. 792–797, 2000.
[18]
E. S. Ogata, M. E. Bussey, and S. Finley, “Altered gas exchange, limited glucose and branched chain amino acids, and hypoinsulinism retard fetal growth in the rat,” Metabolism, vol. 35, no. 10, pp. 970–977, 1986.
[19]
L. A. Joss-Moore, Y. Wang, M. L. Baack et al., “IUGR decreases PPARγ and SETD8 Expression in neonatal rat lung and these effects are ameliorated by maternal DHA supplementation,” Early Human Development, vol. 86, no. 12, pp. 785–791, 2010.
[20]
APS, “Guiding principles for research involving animals and human beings,” American Journal of Physiology, vol. 283, no. 2, pp. R281–R283, 2002.
[21]
M. Baserga, A. L. Bares, M. A. Hale et al., “Uteroplacental insufficiency affects kidney VEGF expression in a model of IUGR with compensatory glomerular hypertrophy and hypertension,” Early Human Development, vol. 85, no. 6, pp. 361–367, 2009.
[22]
F. Scopesi, S. Ciangherotti, P. B. Lantieri et al., “Maternal dietary PUFAs intake and human milk content relationships during the first month of lactation,” Clinical Nutrition, vol. 20, no. 5, pp. 393–397, 2001.
[23]
E. Amusquivar and E. Herrera, “Influence of changes in dietary fatty acids during pregnancy on placental and fetal fatty acid profile in the rat,” Biology of the Neonate, vol. 83, no. 2, pp. 136–145, 2003.
[24]
M. D. Abramoff, P. J. Magelhaes, and S. J. Ram, “Image processing with ImageJ,” Biophotonics International, vol. 11, no. 7, pp. 36–42, 2004.
[25]
L. A. Joss-Moore, Y. Wang, E. M. Ogata et al., “IUGR differentially alters MeCP2 expression and H3K9Me3 of the PPARγ gene in male and female rat lungs during alveolarization,” Birth Defects Research A, vol. 91, no. 8, pp. 672–681, 2011.
[26]
L. Ibá？ez, G. Sebastiani, A. Lopez-Bermejo, M. Díaz, M. D. Gómez-Roig, and F. De Zegher, “Gender specificity of body adiposity and circulating adiponectin, visfatin, insulin, and insulin growth factor-I at term birth: relation to prenatal growth,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 7, pp. 2774–2778, 2008.
[27]
F. Rasmussen, M. Kark, S. Tholin, N. Karnehed, and P. Tynelius, “The Swedish young male twins study: a resource for longitudinal research on risk factors for obesity and cardiovascular diseases,” Twin Research and Human Genetics, vol. 9, no. 6, pp. 883–889, 2006.
[28]
M. Desai, J. Babu, and M. G. Ross, “Programmed metabolic syndrome: prenatal undernutrition and postweaning overnutrition,” American Journal of Physiology, vol. 293, no. 6, pp. R2306–R2314, 2007.
[29]
J. A. Owens, P. Thavaneswaran, M. J. De Blasio, I. C. McMillen, J. S. Robinson, and K. L. Gatford, “Sex-specific effects of placental restriction on components of the metabolic syndrome in young adult sheep,” American Journal of Physiology, vol. 292, no. 6, pp. E1879–E1889, 2007.
[30]
S. Louey, M. L. Cock, and R. Harding, “Long term consequences of low birthweight on postnatal growth, adiposity and brain weight at maturity in sheep,” Journal of Reproduction and Development, vol. 51, no. 1, pp. 59–68, 2005.
[31]
G. Y. Choi, D. N. Tosh, A. Garg, R. Mansano, M. G. Ross, and M. Desai, “Gender-specific programmed hepatic lipid dysregulation in intrauterine growth-restricted offspring,” American Journal of Obstetrics and Gynecology, vol. 196, no. 5, pp. 477.e1–477.e7, 2007.
[32]
G. Medina-Gomez, S. L. Gray, L. Yetukuri et al., “PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism.,” PLoS Genetics, vol. 3, no. 4, article e64, 2007.
[33]
T. T. Tran, Y. Yamamoto, S. Gesta, and C. R. Kahn, “Beneficial effects of subcutaneous fat transplantation on metabolism,” Cell Metabolism, vol. 7, no. 5, pp. 410–420, 2008.
[34]
M. S. Reece, J. A. McGregor, K. G. Allen, and M. A. Harris, “Maternal and perinatal long-chain fatty acids: possible roles in preterm birth,” American Journal of Obstetrics and Gynecology, vol. 176, no. 4, pp. 907–914, 1997.
[35]
M. Van Eijsden, G. Hornstra, M. F. Van Der Wal, T. G. M. Vrijkotte, and G. J. Bonsel, “Maternal n-3, n-6, and trans fatty acid profile early in pregnancy and term birth weight: a prospective cohort study,” American Journal of Clinical Nutrition, vol. 87, no. 4, pp. 887–895, 2008.
[36]
S. F. Olsen, M. L. Osterdal, J. D. Salvig, T. Weber, A. Tabor, and N. J. Secher, “Duration of pregnancy in relation to fish oil supplementation and habitual fish intake: a randomised clinical trial with fish oil,” European Journal of Clinical Nutrition, vol. 61, no. 8, pp. 976–985, 2007.
[37]
B. K. Itariu, M. Zeyda, E. E. Hochbrugger et al., “Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial,” The American Journal of Clinical Nutrition, vol. 96, no. 5, pp. 1137–1149, 2012.
[38]
A. Neuhofer, M. Zeyda, D. Mascher et al., “Impaired local production of pro-resolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation,” Diabetes, 2013.
[39]
P. K. Sharma, A. Bhansali, R. Sialy, S. Malhotra, and P. Pandhi, “Effects of pioglitazone and metformin on plasma adiponectin in newly detected type 2 diabetes mellitus,” Clinical Endocrinology, vol. 65, no. 6, pp. 722–728, 2006.
[40]
A. Tsuchida, T. Yamauchi, S. Takekawa et al., “Peroxisome proliferator-activated receptor (PPAR)α activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARα, PPARγ, and their combination,” Diabetes, vol. 54, no. 12, pp. 3358–3370, 2005.
[41]
P. A. Kern, G. B. Di Gregorio, T. Lu, N. Rassouli, and G. Ranganathan, “Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-α expression,” Diabetes, vol. 52, no. 7, pp. 1779–1785, 2003.
[42]
N. Rasouli and P. A. Kern, “Adipocytokines and the metabolic complications of obesity,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 11, supplement, pp. s64–s73, 2008.
[43]
D. D. Briana and A. Malamitsi-Puchner, “Intrauterine growth restriction and adult disease: the role of adipocytokines,” European Journal of Endocrinology, vol. 160, no. 3, pp. 337–347, 2009.
[44]
A. López-Bermejo, “Insulin resistance after prenatal growth restriction: is it mediated by adiponectin deficiency?” Clinical Endocrinology, vol. 64, no. 5, pp. 479–480, 2006.
[45]
T. Yamauchi and T. Kadowaki, “Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases,” International Journal of Obesity, vol. 32, no. 7, pp. S13–S18, 2008.
[46]
C. Kim, J. Park, J. Park et al., “Comparison of body fat composition and serum adiponectin levels in diabetic obesity and non-diabetic obesity,” Obesity, vol. 14, no. 7, pp. 1164–1171, 2006.
[47]
S. Perrini, L. Laviola, A. Cignarelli et al., “Fat depot-related differences in gene expression, adiponectin secretion, and insulin action and signalling in human adipocytes differentiated in vitro from precursor stromal cells,” Diabetologia, vol. 51, no. 1, pp. 155–164, 2008.
