Fetal Programming of Adipose Tissue: Effects of Intrauterine Growth Restriction and Maternal Obesity/High-Fat Diet

ABSTRACT

A newly recognized primary cause of obesity epidemic is the developmental programming effects of (1) intrauterine growth-restricted (IUGR) newborns exposed in utero to undernutrition, and (2) normal or excessive weight newborns exposed to maternal obesity and high-fat (HF) diets. The mechanisms contributing to offspring obesity have been extensively studied in animal models with adipose tissue identified as one of the principal targets of programming. IUGR and HF offspring exhibit programmed adipocytes, such that an intrinsic enhanced lipogenesis and adipocyte proliferation contribute to the development of obesity. This is attributed to early induction of adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)γ, whose activity is enhanced under limited or excess nutrient availability. Nonetheless, this occurs via different mechanisms involving PPARγ coregulators: In IUGR, it is upregulation of coactivators, whereas in HF newborns, it is downregulation of corepressors. Thus preventive therapeutic interventions will require target-specific modalities that depend on the primary etiology.

KEYWORDS

Adipogenesis - lipogenesis - PPARγ - obesity

REFERENCES

• 1 James P T, Leach R, Kalamara E, Shayeghi M. The worldwide obesity epidemic.  Obes Res. 2001;  9 (Suppl 4) 228S-233S
• 2 Ogden C L, Yanovski S Z, Carroll M D, Flegal K M. The epidemiology of obesity.  Gastroenterology. 2007;  132 (6) 2087-2102
• 3 Ehrenberg H M, Mercer B M, Catalano P M. The influence of obesity and diabetes on the prevalence of macrosomia.  Am J Obstet Gynecol. 2004;  191 (3) 964-968
• 4 American College of Obstetricians and Gynecologists . ACOG Committee Opinion number 315, September 2005. Obesity in pregnancy.  Obstet Gynecol. 2005;  106 (3) 671-675
• 5 Guo S S, Wu W, Chumlea W C, Roche A F. Predicting overweight and obesity in adulthood from body mass index values in childhood and adolescence.  Am J Clin Nutr. 2002;  76 (3) 653-658
• 6 Barker D J, Eriksson J G, Forsén T, Osmond C. Fetal origins of adult disease: strength of effects and biological basis.  Int J Epidemiol. 2002;  31 (6) 1235-1239
• 7 Hales C N, Barker D J. The thrifty phenotype hypothesis.  Br Med Bull. 2001;  60 5-20
• 8 Desai M, Hales C N. Role of fetal and infant growth in programming metabolism in later life.  Biol Rev Camb Philos Soc. 1997;  72 (2) 329-348
• 9 Ross M G, Desai M. Gestational programming: population survival effects of drought and famine during pregnancy.  Am J Physiol Regul Integr Comp Physiol. 2005;  288 (1) R25-R33
• 10 Flier J S. The adipocyte: storage depot or node on the energy information superhighway?.  Cell. 1995;  80 (1) 15-18
• 11 Reilly M P, Rader D J. The metabolic syndrome: more than the sum of its parts?.  Circulation. 2003;  108 (13) 1546-1551
• 12 Gluckman P D, Hanson M A, Morton S M, Pinal C S. Life-long echoes—a critical analysis of the developmental origins of adult disease model.  Biol Neonate. 2005;  87 (2) 127-139
• 13 Harding J E. The nutritional basis of the fetal origins of adult disease.  Int J Epidemiol. 2001;  30 (1) 15-23
• 14 Barker D J, Hales C N, Fall C H, Osmond C, Phipps K, Clark P M. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth.  Diabetologia. 1993;  36 (1) 62-67
• 15 Ravelli G P, Stein Z A, Susser M W. Obesity in young men after famine exposure in utero and early infancy.  N Engl J Med. 1976;  295 (7) 349-353
• 16 Simmons R. Perinatal programming of obesity.  Semin Perinatol. 2008;  32 (5) 371-374
• 17 Boney C M, Verma A, Tucker R, Vohr B R. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus.  Pediatrics. 2005;  115 (3) e290-e296
• 18 Oken E, Rifas-Shiman S L, Field A E, Frazier A L, Gillman M W. Maternal gestational weight gain and offspring weight in adolescence.  Obstet Gynecol. 2008;  112 (5) 999-1006
• 19 Surkan P J, Hsieh C C, Johansson A L, Dickman P W, Cnattingius S. Reasons for increasing trends in large for gestational age births.  Obstet Gynecol. 2004;  104 (4) 720-726
• 20 Armitage J A, Poston L, Taylor P D. Developmental origins of obesity and the metabolic syndrome: the role of maternal obesity.  Front Horm Res. 2008;  36 73-84
• 21 Pettitt D J, Jovanovic L. Birth weight as a predictor of type 2 diabetes mellitus: the U-shaped curve.  Curr Diab Rep. 2001;  1 (1) 78-81
• 22 Ong K K. Size at birth, postnatal growth and risk of obesity.  Horm Res. 2006;  65 (Suppl 3) 65-69
• 23 Pettitt D J, Jovanovic L. Low birth weight as a risk factor for gestational diabetes, diabetes, and impaired glucose tolerance during pregnancy.  Diabetes Care. 2007;  30 (Suppl 2) S147-S149
• 24 Launer L J, Hofman A, Grobbee D E. Relation between birth weight and blood pressure: longitudinal study of infants and children.  BMJ. 1993;  307 (6917) 1451-1454
• 25 McMillen I C, Robinson J S. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.  Physiol Rev. 2005;  85 (2) 571-633
• 26 Hales C N, Desai M, Ozanne S E. The thrifty phenotype hypothesis: how does it look after 5 years?.  Diabet Med. 1997;  14 (3) 189-195
• 27 Seckl J R, Meaney M J. Glucocorticoid programming.  Ann N Y Acad Sci. 2004;  1032 63-84
• 28 Bol V V, Delattre A I, Reusens B, Raes M, Remacle C. Forced catch-up growth after fetal protein restriction alters the adipose tissue gene expression program leading to obesity in adult mice.  Am J Physiol Regul Integr Comp Physiol. 2009;  297 (2) R291-R299
• 29 Desai M, Gayle D, Babu J, Ross M G. Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition.  Am J Physiol Regul Integr Comp Physiol. 2005;  288 (1) R91-R96
• 30 Desai M, Gayle D, Babu J, Ross M G. Permanent reduction in heart and kidney organ growth in offspring of undernourished rat dams.  Am J Obstet Gynecol. 2005;  193 (3 Pt 2) 1224-1232
• 31 Chang G Q, Gaysinskaya V, Karatayev O, Leibowitz S F. Maternal high-fat diet and fetal programming: increased proliferation of hypothalamic peptide-producing neurons that increase risk for overeating and obesity.  J Neurosci. 2008;  28 (46) 12107-12119
• 32 Bruce K D, Cagampang F R, Argenton M et al.. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression.  Hepatology. 2009;  50 (6) 1796-1808
• 33 Howie G J, Sloboda D M, Kamal T, Vickers M H. Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet.  J Physiol. 2009;  587 (Pt 4) 905-915
• 34 Férézou-Viala J, Roy A F, Sérougne C et al.. Long-term consequences of maternal high-fat feeding on hypothalamic leptin sensitivity and diet-induced obesity in the offspring.  Am J Physiol Regul Integr Comp Physiol. 2007;  293 (3) R1056-R1062
• 35 Samuelsson A M, Matthews P A, Argenton M et al.. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming.  Hypertension. 2008;  51 (2) 383-392
• 36 Jones A P, Simson E L, Friedman M I. Gestational undernutrition and the development of obesity in rats.  J Nutr. 1984;  114 (8) 1484-1492
• 37 Desai M, Li T, Han G, Guberman C, Ross M G. Maternal obesity and increased risk of offspring metabolic syndrome.  Reprod Sci. 2010;  17 (Suppl 3) 104, 139
• 38 Bouret S G, Draper S J, Simerly R B. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice.  J Neurosci. 2004;  24 (11) 2797-2805
• 39 Bouret S G, Simerly R B. Developmental programming of hypothalamic feeding circuits.  Clin Genet. 2006;  70 (4) 295-301
• 40 Ahima R S, Prabakaran D, Flier J S. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function.  J Clin Invest. 1998;  101 (5) 1020-1027
• 41 Bouret S G, Simerly R B. Minireview: Leptin and development of hypothalamic feeding circuits.  Endocrinology. 2004;  145 (6) 2621-2626
• 42 Campfield L A, Smith F J, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks.  Science. 1995;  269 (5223) 546-549
• 43 Coupé B, Amarger V, Grit I, Benani A, Parnet P. Nutritional programming affects hypothalamic organization and early response to leptin.  Endocrinology. 2010;  151 (2) 702-713
• 44 Yousheng Jia, Nguyen T, Desai M, Ross M G. Programmed alterations in hypothalamic neuronal orexigenic responses to ghrelin following gestational nutrient restriction.  Reprod Sci. 2008;  15 (7) 702-709
• 45 Desai M, Gayle D, Han G, Ross M G. Programmed hyperphagia due to reduced anorexigenic mechanisms in intrauterine growth-restricted offspring.  Reprod Sci. 2007;  14 (4) 329-337
• 46 Desai M, Ti L, Ross M G. Fetal hypothalamic neuroprogenitor cell culture: preferential differentiation paths induced by leptin and insulin.  Endocrinology. 2011;  in press
• 47 Desai M, Li T, Ross M G. Hypothalamic neurosphere progenitor cells in low birth-weight rat newborns: neurotrophic effects of leptin and insulin.  Brain Res. 2011;  1378 29-42
• 48 Kirk S L, Samuelsson A M, Argenton M et al.. Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring.  PLoS ONE. 2009;  4 (6) e5870
• 49 Wabitsch M. The acquisition of obesity: insights from cellular and genetic research.  Proc Nutr Soc. 2000;  59 (2) 325-330
• 50 Gregoire F M, Smas C M, Sul H S. Understanding adipocyte differentiation.  Physiol Rev. 1998;  78 (3) 783-809
• 51 Hausman D B, DiGirolamo M, Bartness T J, Hausman G J, Martin R J. The biology of white adipocyte proliferation.  Obes Rev. 2001;  2 (4) 239-254
• 52 Rosen E D, Spiegelman B M. Molecular regulation of adipogenesis.  Annu Rev Cell Dev Biol. 2000;  16 145-171
• 53 Spiegelman B M, Flier J S. Adipogenesis and obesity: rounding out the big picture.  Cell. 1996;  87 (3) 377-389
• 54 Auwerx J, Martin G, Guerre-Millo M, Staels B. Transcription, adipocyte differentiation, and obesity.  J Mol Med. 1996;  74 (7) 347-352
• 55 Fajas L, Fruchart J C, Auwerx J. Transcriptional control of adipogenesis.  Curr Opin Cell Biol. 1998;  10 (2) 165-173
• 56 Rosen E D, Spiegelman B M. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth.  J Biol Chem. 2001;  276 (41) 37731-37734
• 57 Morrison R F, Farmer S R. Insights into the transcriptional control of adipocyte differentiation.  J Cell Biochem. 1999;  33 (Suppl 32) 59-67
• 58 Farmer S R. Regulation of PPARgamma activity during adipogenesis.  Int J Obes (Lond). 2005;  29 (Suppl 1) S13-S16
• 59 Darlington G J, Ross S E, MacDougald O A. The role of C/EBP genes in adipocyte differentiation.  J Biol Chem. 1998;  273 (46) 30057-30060
• 60 Lane M D, Lin F T, MacDougald O A, Vasseur-Cognet M. Control of adipocyte differentiation by CCAAT/enhancer binding protein alpha (C/EBP alpha).  Int J Obes Relat Metab Disord. 1996;  20 (Suppl 3) S91-S96
• 61 Fajas L, Schoonjans K, Gelman L et al.. Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism.  Mol Cell Biol. 1999;  19 (8) 5495-5503
• 62 Kim J B, Spiegelman B M. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism.  Genes Dev. 1996;  10 (9) 1096-1107
• 63 Walczak R, Tontonoz P. PPARadigms and PPARadoxes: expanding roles for PPARgamma in the control of lipid metabolism.  J Lipid Res. 2002;  43 (2) 177-186
• 64 Kim J B, Wright H M, Wright M, Spiegelman B M. ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand.  Proc Natl Acad Sci U S A. 1998;  95 (8) 4333-4337
• 65 Kim J B, Sarraf P, Wright M et al.. Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1.  J Clin Invest. 1998;  101 (1) 1-9
• 66 Boizard M, Le Liepvre X, Lemarchand P, Foufelle F, Ferré P, Dugail I. Obesity-related overexpression of fatty-acid synthase gene in adipose tissue involves sterol regulatory element-binding protein transcription factors.  J Biol Chem. 1998;  273 (44) 29164-29171
• 67 Samra J S. Sir David Cuthbertson Medal Lecture. Regulation of lipid metabolism in adipose tissue.  Proc Nutr Soc. 2000;  59 (3) 441-446
• 68 Vázquez-Vela M E, Torres N, Tovar A R. White adipose tissue as endocrine organ and its role in obesity.  Arch Med Res. 2008;  39 (8) 715-728
• 69 Bulcão C, Ferreira S R, Giuffrida F M, Ribeiro-Filho F F. The new adipose tissue and adipocytokines.  Curr Diabetes Rev. 2006;  2 (1) 19-28
• 70 Bahceci M, Gokalp D, Bahceci S, Tuzcu A, Atmaca S, Arikan S. The correlation between adiposity and adiponectin, tumor necrosis factor alpha, interleukin-6 and high sensitivity C-reactive protein levels. Is adipocyte size associated with inflammation in adults?.  J Endocrinol Invest. 2007;  30 (3) 210-214
• 71 Lefebvre A M, Laville M, Vega N et al.. Depot-specific differences in adipose tissue gene expression in lean and obese subjects.  Diabetes. 1998;  47 (1) 98-103
• 72 Freedland E S. Role of a critical visceral adipose tissue threshold (CVATT) in metabolic syndrome: implications for controlling dietary carbohydrates: a review.  Nutr Metab (Lond). 2004;  1 (1) 12
• 73 Shi H, Clegg D J. Sex differences in the regulation of body weight.  Physiol Behav. 2009;  97 (2) 199-204
• 74 Jensen M D. Lipolysis: contribution from regional fat.  Annu Rev Nutr. 1997;  17 127-139
• 75 Sewter C P, Blows F, Vidal-Puig A, O'Rahilly S. Regional differences in the response of human pre-adipocytes to PPARgamma and RXRalpha agonists.  Diabetes. 2002;  51 (3) 718-723
• 76 Adams M, Montague C T, Prins J B et al.. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation.  J Clin Invest. 1997;  100 (12) 3149-3153
• 77 Hauner H, Wabitsch M, Pfeiffer E F. Differentiation of adipocyte precursor cells from obese and nonobese adult women and from different adipose tissue sites.  Horm Metab Res Suppl. 1988;  19 (Suppl) 35-39
• 78 Danforth Jr E. Failure of adipocyte differentiation causes type II diabetes mellitus?.  Nat Genet. 2000;  26 (1) 13
• 79 Frayn K N. Adipose tissue as a buffer for daily lipid flux.  Diabetologia. 2002;  45 (9) 1201-1210
• 80 Shepherd P R, Crowther N J, Desai M, Hales C N, Ozanne S E. Altered adipocyte properties in the offspring of protein malnourished rats.  Br J Nutr. 1997;  78 (1) 121-129
• 81 Bieswal F, Ahn M T, Reusens B et al.. The importance of catch-up growth after early malnutrition for the programming of obesity in male rat.  Obesity (Silver Spring). 2006;  14 (8) 1330-1343
• 82 Guan H, Arany E, van Beek J P et al.. Adipose tissue gene expression profiling reveals distinct molecular pathways that define visceral adiposity in offspring of maternal protein-restricted rats.  Am J Physiol Endocrinol Metab. 2005;  288 (4) E663-E673
• 83 Desai M, Guang Han, Ferelli M, Kallichanda N, Lane R H. Programmed upregulation of adipogenic transcription factors in intrauterine growth-restricted offspring.  Reprod Sci. 2008;  15 (8) 785-796
• 84 Yee J K, Lee P W, Ross M G, Desai M. Enhancement of de novo fatty acid synthesis in IUGR adipose tissue prior to onset of programmed obesity.  Reprod Sci. 2010;  17 (Suppl 3) 104A, 137
• 85 Yang T, Fu M, Pestell R, Sauve A A. SIRT1 and endocrine signaling.  Trends Endocrinol Metab. 2006;  17 (5) 186-191
• 86 Picard F, Kurtev M, Chung N et al.. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.  Nature. 2004;  429 (6993) 771-776
• 87 Klöting N, Blüher M. Extended longevity and insulin signaling in adipose tissue.  Exp Gerontol. 2005;  40 (11) 878-883
• 88 Powell E, Kuhn P, Xu W. Nuclear receptor cofactors in PPARgamma-mediated adipogenesis and adipocyte energy metabolism.  PPAR Res. 2007;  2007 53843
• 89 Feige J N, Auwerx J. Transcriptional coregulators in the control of energy homeostasis.  Trends Cell Biol. 2007;  17 (6) 292-301
• 90 Desai M, Lane R H, Han G, Ross M G. Failure to suppress adipogenic transcription factor (PPARy) activity leads to programmed obesity in IUGR offspring.  Reprod Sci. 2010;  15 (Suppl 1) 76A
• 91 Desai M, Han G, Joss-Moore L, Ross M G, Lane R H. (SIRT1) mediated mechanisms for programmed enhanced adipogenesis in intrauterine growth restricted newborns. Presented at: the Pediatric Academic Society Annual Meeting; 2008; Honolulu, Hawaii
• 92 Desai M, Lane R H, Han G, Ross M G. Response of IUGR primary cell culture adipocytes to PPARy activator-ligand and repressor-ligand mechanism of programmed obesity.  Reprod Sci. 2008;  15 (Suppl 1) 194A
• 93 Choy L, Skillington J, Derynck R. Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation.  J Cell Biol. 2000;  149 (3) 667-682
• 94 Desai M, Lane R H, Han G, Ross M G. Mechanism of enhanced adipogenesis in intrauterine growth restricted offspring: dysregulation of adipogenic function and reduced response to PPARã modulators.  Early Hum Dev. 2007;  83 S48
• 95 Plagemann A, Harder T, Dudenhausen J W. The diabetic pregnancy, macrosomia, and perinatal nutritional programming.  Nestle Nutr Workshop Ser Pediatr Program. 2008;  61 91-102
• 96 Desai M, Han G, Li T, Ross M G. Transcriptional regulation of adipogenesis in newborns exposed to maternal obesity.  Reprod Sci. 2010;  17 (Suppl) 217A, 532A
• 97 Wakabayashi K, Okamura M, Tsutsumi S et al.. The peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha heterodimer targets the histone modification enzyme PR-Set7/Setd8 gene and regulates adipogenesis through a positive feedback loop.  Mol Cell Biol. 2009;  29 (13) 3544-3555
• 98 Wright H M, Clish C B, Mikami T et al.. A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation.  J Biol Chem. 2000;  275 (3) 1873-1877