Skip to main content Accessibility help

Hypothalamic expression of genes for appetite regulators and estrogen α, estrogen β and leptin receptors in obese dams and their fetuses

  • A. B. Breton (a1), R. R. Cockrum (a1), K. J. Austin (a1), K. M. Cammack (a1), S. P. Ford (a2), B. W. Hess (a1), G. E. Moss (a1), P. W. Nathanielsz (a3) and B. M. Alexander (a1)...


Under- and over-nutrition during gestation may influence fetal hypothalamic development resulting in individuals predisposed to adverse health effects. This study examined fetuses from obese and control ewes to determine whether dam obesity alters hypothalamic expression of fetal appetite regulatory genes. A second objective was to contrast the expression of appetite regulatory genes in ewes that become the most obese to those that remained in moderate body condition on the same energy-rich diet. Multiparous, western white-faced ewes were weighed and individually fed 100% (control) or 150% (obese) of National Research Council requirements from day 60 before mating until day 75 of gestation. At day 75 of gestation, fetuses were collected and weighed. Hypothalamic tissue from fetal lambs and dams was collected and frozen for mRNA extraction. Dam obesity (P ⩾ 0.16), fetal sex (P ⩾ 0.44) or their interaction (P ⩾ 0.42) did not affect the relative expression of fetal hypothalamic regulators of appetite, including neuropeptide Y, agouti-related protein, pro-opiomelanocortin, cocaine- and amphetamine-regulated transcript and receptors for leptin. Maternal obesity at day 75 of gestation in ewes did not affect developmental mechanisms responsible for the expression of fetal appetite regulatory genes and would not be expected to predispose offspring to adult-onset obesity through disrupted appetite regulation at this developmental time point. In the ewe, appetite regulatory genes did not differ (P > 0.20) with ewe adiposity; however, expression of estrogen receptor α, but not β (P = 0.37), in the medial basal hypothalamus was greater (P = 0.04) in obese than in control ewes.


Corresponding author


Hide All
Adam, CL, Findlay, PA 2010. Decreased blood–brain leptin transfer in an ovine model of obesity and weight loss: resolving the cause of leptin resistance. International Journal of Obesity 34, 980988.
Clarke, IJ 2008. Models of ‘obesity’ in large animals and birds. Frontiers in Hormone Research 36, 107117.
Coupe, B, Amarger, V, Grit, I, Benani, A, Parnet, P 2010. Nutrtional programming affects hypothalamic organization and early response to leptin. Endocrinology 151, 702713.
Fischer-Posovszky, P, Wabitsch, M, Hochberg, Z 2007. Endocrinology of adipose tissue – an update. Hormone Metabolism Research 39, 314321.
Ford, SP, Zhang, L, Zhu, M, Miller, MM, Smith, DT, Hess, BW, Moss, GE, Nathanielsz, PW, Nijland, MJ 2009. Maternal obesity accelerates fetal pancreatic β-cell but not α-cell development in sheep: prenatal consequences. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 297, R835R843.
Fowden, AL, Forhead, AJ 2009. Hormones as epigenetic signals in developmental programming. Experimental Physiology 94, 607625.
George, LA, Uthlaut, AB, Long, NM, Zhang, L, Ma, Y, Smith, DT, Nathanielsz, PW, Ford, SP 2010. Different levels of overnutrition and weight gain during pregnancy have differential effects on fetal growth and organ development. Reproductive Biology and Endocrinology 8, 75. Retrieved May 2, 2011, from
Grove, KL, Grayson, BE, Glavas, MM, Xiao, XQ, Smith, MS 2005. Development of metabolic systems. Physiology and Behavior 86, 646660.
Guo-Qing, C, Gaysinskaya, V, Karatayev, O, Leibowitz, SF 2008. Maternal high-fat diet and fetal programming: increased proliferation of hypothalamic peptide-producing neurons that increase risk for overeating and obesity. The Journal of Neuroscience 28, 1210712119.
Hewitt, SC, Deroo, BJ, Hansen, K, Collins, J, Grissom, S, Afshari, CA, Korach, KS 2003. Estrogen receptor-dependent genomic responses in the uterus mirror the biphasic physiological response to estrogen. Molecular Endocrinology 17, 20702083.
Kahlert, S, Nuedling, S, Van Eickels, M, Vetter, H, Meyer, R, Grohe, C 2000. Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway. The Journal of Biological Chemistry 275, 1844718453.
Kirk, SL, Samuelsson, AM, Argenton, M, Dhonye, H, Kalamatianos, T, Poston, L, Taylor, PD, Coen, CW 2009. Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring. PLoS ONE 4, e5870.
Lewis, DS, Bertrand, HA, McMahan, CA, McGill, HC Jr, Carey, KD, Masoro, EJ 1986. Preweaning food intake influences the adiposity of young adult baboons. The Journal of Clinical Investigation 78, 899905.
Livak, KJ, Schmittgen, TD 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ddCT method. Applied Biosystems, Methods 25, 402408.
Long, NM, George, LA, Uthlaut, AB, Smith, DT, Nijland, MJ, Nathanielsz, PW, Ford, SP 2010. Maternal obesity and increased nutrient intake before and during gestation in the ewe results in altered growth, adiposity, and glucose tolerance in adult offspring. Journal of Animal Science 88, 35463553.
McMillen, IC, Adam, CL, Muhlhausler, BS 2005. Early origins of obesity: programming the appetite regulatory system. Journal of Physiology 565, 917.
Morris, DL, Rui, L 2009. Recent advances in understanding leptin signaling and leptin resistance. American Journal of Physiology Endocrinology and Metabolism 297, E1247E1259.
Moss, GE, Crowder, ME, Nett, TM 1981. GnRH-receptor interaction. VI. Effect of progesterone and estradiol on hypophyseal receptors for GnRH, and serum and hypophyseal concentrations of gonadotropins in ovariectomized ewes. Biology of Reproduction 25, 938944.
Muhlhausler, BS, Adam, CL, Findlay, PA, Duffield, JA, McMillen, IC 2006. Increased maternal nutrition alters development of the appetite-regulating network in the brain. The FASEB Journal 20, E556E565.
Muhlhausler, BS, McMillen, IC, Rouzaud, G, Findlay, PA, Marrocco, EM, Rhind, SM, Adam, CL 2004. Appetite regulatory neuropeptides are expressed in the sheep hypothalamus before birth. Journal of Neuroendocrinology 16, 502507.
Muhlhausler, BS, Adam, CL, Marrocco, EM, Findlay, PA, Roberts, CT, McFarlane, JR, Kauter, KG, McMillen, IC 2005. Impact of glucose infusion on the structural and functional characteristics of adipose tissue and on hypothalamic gene expression for appetite regulatory neuropeptides in the sheep fetus during late gestation. Journal of Physiology 565, 185195.
National Research Council (NRC) 1990. Nutrient requirements of sheep, 6th edition. National Academy, Washington, DC.
Norman, RJ, Clark, AM 1998. Obesity and reproductive disorders: a review. Reproduction, Fertility and Development 10, 5563.
Rozen, S, Skaletsky, H 2000. Primer 3 on the www for general users and biologist programmers. In Bioinformatics methods and protocols: methods in molecular biology (ed. S Krawetz and S Misener), pp. 365386. Human Press, Totowa, NJ.
Sanson, DW, West, TR, Tatman, WR, Riley, ML, Judkins, MB, Moss, GE 1993. Relationship of body composition of mature ewes with condition score and body weight. Journal of Animal Science 71, 11121116.
Stevens, A, Begum, G, Cook, A, Connor, K, Rumball, C, Oliver, M, Challis, J, Bloomfield, F, White, A 2010. Epigenetic changes in the hypothalamic proopiomelanocortin and glucocorticoid receptor genes in the ovine fetus after periconceptional undernutrition. Endocrinology 151, 36523664.
Tatman, WR, Judkins, MB, Krysl, LJ, Moss, GE 1991. Gastrointestinal digesta passage and fermentation patterns associated with restricted intake of a low-quality forage in ewes. Small Ruminant Research 4, 393399.
Wagner, CG, McMahon, CD, Marks, DL, Daniel, JA, Steele, B, Sartin, JL 2004. A role for agouti-related protein in appetite regulation in a species with continuous nutrient delivery. Neuroendocrinology 80, 210218.
Zhu, MJ, Han, B, Tong, J, Ma, C, Kimzey, JM, Underwood, KR, Xiao, Y, Hess, BW, Ford, SP, Nathanielsz, PW, Du, M 2008. AMP-activated protein kinase signalling pathways are down regulated and skeletal muscle development impaired in fetuses of obese, over-nourished sheep. Journal of Physiology 586, 26512664.



Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed