Hostname: page-component-8448b6f56d-qsmjn Total loading time: 0 Render date: 2024-04-19T04:25:03.580Z Has data issue: false hasContentIssue false
  • English
  • Français

Epigenetic changes in hypothalamic appetite regulatory genes may underlie the developmental programming for obesity in rat neonates subjected to a high-carbohydrate dietary modification

Published online by Cambridge University Press:  24 June 2013

S. Mahmood ,
D. J. Smiraglia ,
M. Srinivasan  and
M. S. Patel
S. Mahmood
Affiliation:
Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, USA
D. J. Smiraglia
Affiliation:
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, USA
M. Srinivasan
Affiliation:
Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, USA
M. S. Patel*
Affiliation:
Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, USA
*
Address for correspondence: M. S. Patel, Department of Biochemistry, School of Medicine and Biomedical Sciences, 140 Farber Hall, 3435 Main Street, Buffalo, NY 14214, USA. Email mspatel@buffalo.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

Earlier, we showed that rearing of newborn rats on a high-carbohydrate (HC) milk formula resulted in the onset of hyperinsulinemia, its persistence in the post-weaning period and adult-onset obesity. DNA methylation of CpG dinucleotides in the proximal promoter region and modifications in the N-terminal tail of histone 3 associated with the neuropeptide Y (Npy) and pro-opiomelanocortin (Pomc) genes were investigated to decipher the molecular mechanisms supporting the development of obesity in HC females. Although there were no differences in the methylation status of CpG dinucleotides in the proximal promoter region of the Pomc gene, altered methylation of specific CpG dinucleotides proximal to the transcription start site was observed for the Npy gene in the hypothalami of 16- and 100-day-old HC rats compared with their methylation status in mother-fed (MF) rats. Investigation of histone tail modifications on hypothalamic chromatin extracts from 16-day-old rats indicated decreased acetylation of lysine 9 in histone 3 (H3K9) for the Pomc gene and increased acetylation for the same residue for the Npy gene, without changes in histone methylation (H3K9) in both genes in HC rats. These findings are consistent with the changes in the levels of Npy and Pomc mRNAs in the hypothalami of HC rats compared with MF animals. Our results suggest that epigenetic modifications could contribute to the altered gene expression of the Npy and Pomc genes in the hypothalami of HC rats and could be a mechanism leading to hyperphagia and the development of obesity in adult female HC rats.

Keywords

development of obesityepigeneticshigh-carbohydrate formulaneuropeptide genessuckling period
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 4 , Issue 6 , December 2013 , pp. 479 - 490
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Flegal, KM, Carroll, MD, Ogden, CL, Curtin, LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010; 303, 235–241.Google Scholar
2.Fernandez-Twinn, DS, Ozanne, SE. Early life nutrition and metabolic programming. Annals NY Acad Sci. 2010; 1212, 78–96.Google Scholar
3.Guilloteau, P, Zabielski, R, Hammon, HM, Metges, CC. Adverse effects of nutritional programming during prenatal and early postnatal life, some aspects of regulation and potential prevention and treatments. J Physiol Pharmacol (Polish Physiol Soc). 2009; 60(Suppl 3), 17–35.Google Scholar
4.Plagemann, A, Davidowa, H, Harder, T, Dudenhausen, JW. Developmental programming of the hypothalamus: a matter of insulin. A comment on: Horvath, T. L., Bruning, J. C.: Developmental programming of the hypothalamus: a matter of fat. Nat Med. (2006); 12, 52–53. Neuro Endocrinol Lett. 2006; 27, 70–72.Google Scholar
5.Palou, M, Pico, C, McKay, JA, et al. Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic pro-opiomelanocortin gene. Br J Nutr. 2011; 106, 769–778.CrossRefGoogle ScholarPubMed
6.Srinivasan, M, Patel, MS. Metabolic programming in the immediate postnatal period. Trends Endocrinol Metab. 2008; 19, 146–152.Google Scholar
7.Patel, MS, Srinivasan, M. Metabolic programming in the immediate postnatal life. Ann Nutr Metab. 2011; 58(Suppl 2), 18–28.CrossRefGoogle ScholarPubMed
8.Grove, KL, Allen, S, Grayson, BE, Smith, MS. Postnatal development of the hypothalamic neuropeptide Y system. Neuroscience. 2003; 116, 393–406.Google Scholar
9.Kozak, R, Richy, S, Beck, B. Persistent alterations in neuropeptide Y release in the paraventricular nucleus of rats subjected to dietary manipulation during early life. Eur J Neurosci. 2005; 21, 2887–2892.Google Scholar
10.Davidowa, H, Plagemann, A. Decreased inhibition by leptin of hypothalamic arcuate neurons in neonatally overfed young rats. Neuroreport. 2000; 11, 2795–2798.Google Scholar
11.Davidowa, H, Plagemann, A. Insulin resistance of hypothalamic arcuate neurons in neonatally overfed rats. Neuroreport. 2007; 18, 521–524.CrossRefGoogle ScholarPubMed
12.Plagemann, A, Harder, T, Rake, A, et al. Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats. J Neuroendocrinol. 1999; 11, 541–546.CrossRefGoogle ScholarPubMed
13.Newell-Price, J, King, P, Clark, AJ. The CpG island promoter of the human proopiomelanocortin gene is methylated in nonexpressing normal tissue and tumors and represses expression. Mol Endocrinol. 2001; 15, 338–348.Google Scholar
14.Ho, SM, Tang, WY. Techniques used in studies of epigenome dysregulation due to aberrant DNA methylation: an emphasis on fetal-based adult diseases. Reprod Toxicol. 2007; 23, 267–282.Google Scholar
15.Srinivasan, M, Mitrani, P, Sadhanandan, G, et al. A high-carbohydrate diet in the immediate postnatal life of rats induces adaptations predisposing to adult-onset obesity. J Endocrinol. 2008; 197, 565–574.CrossRefGoogle ScholarPubMed
16.Mitrani, P, Srinivasan, M, Dodds, C, Patel, MS. Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model. Am J Physiol Endocrinol Metab. 2007; 292, E1364–E1377.Google Scholar
17.Vadlamudi, S, Kalhan, SC, Patel, MS. Persistence of metabolic consequences in the progeny of rats fed a HC formula in their early postnatal life. Am J Physiol. 1995; 269, E731–E738.Google Scholar
18.Srinivasan, M, Dodds, C, Ghanim, H, et al. Maternal obesity and fetal programming: effects of a high-carbohydrate nutritional modification in the immediate postnatal life of female rats. Am J Physiol Endocrinol Metab. 2008; 295, E895–E903.Google Scholar
19.Hiremagalur, BK, Vadlamudi, S, Johanning, GL, Patel, MS. Long-term effects of feeding high carbohydrate diet in pre-weaning period by gastrostomy: a new rat model for obesity. Int J Obes Relat Metab Disord. 1993; 17, 495–502.Google Scholar
20.Vadlamudi, S, Hiremagalur, BK, Tao, L, et al. Long-term effects on pancreatic function of feeding a HC formula to rats during the preweaning period. Am J Physiol. 1993; 265, E565–E571.Google Scholar
21.Livak, KJ, Schmittgen, TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001; 25, 402–408.Google Scholar
22.Ehrich, M, Nelson, MR, Stanssens, P, et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc Natl Acad Sci U S A. 2005; 102, 15785–15790.CrossRefGoogle ScholarPubMed
23.Li, LC, Dahiya, R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002; 18, 1427–1431.Google Scholar
24.Farre, D, Roset, R, Huerta, M, et al. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 2003; 31, 3651–3653.CrossRefGoogle ScholarPubMed
25.Messeguer, X, Escudero, R, Farre, D, et al. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002; 18, 333–334.Google Scholar
26.Plagemann, A, Harder, T, Brunn, M, et al. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol. 2009; 587, 4963–4976.Google Scholar
27.Portela, A, Esteller, M. Epigenetic modifications and human disease. Nat Biotechnol. 2010; 28, 1057–1068.Google Scholar
28.Jaskelioff, M, Peterson, CL. Chromatin and transcription: histones continue to make their marks. Nat Cell Biol. 2003; 5, 395–399.Google Scholar
29.Jenuwein, T. The epigenetic magic of histone lysine methylation. FEBS J. 2006; 273, 3121–3135.Google Scholar
30.Hanson, M, Godfrey, KM, Lillycrop, KA, Burdge, GC, Gluckman, PD. Developmental plasticity and developmental origins of non-communicable disease: theoretical considerations and epigenetic mechanisms. Prog Biophys Mol Biol. 2011; 106, 272–280.Google Scholar
31.Lillycrop, KA, Burdge, GC. Epigenetic changes in early life and future risk of obesity. Int J Obes (Lond). 2011; 35, 72–83.Google Scholar
32.Vucetic, Z, Kimmel, J, Totoki, K, Hollenbeck, E, Reyes, TM. Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology. 2010; 151, 4756–4764.Google Scholar
33.Lillycrop, KA, Slater-Jefferies, JL, Hanson, MA, et al. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr. 2007; 97, 1064–1073.Google Scholar
34.Dolinoy, DC, Das, R, Weidman, JR, Jirtle, RL. Metastable epialleles, imprinting, and the fetal origins of adult diseases. Pediatr Res. 2007; 61, 30R–37R.CrossRefGoogle ScholarPubMed
35.Waterland, RA, Jirtle, RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003; 23, 5293–5300.Google Scholar
36.Champagne, FA, Weaver, IC, Diorio, J, et al. Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinol. 2006; 147, 2909–2915.CrossRefGoogle ScholarPubMed
37.Bagot, RC, Zhang, TY, Wen, X, et al. Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat. Proc Natl Acad Sci U S A. 2012; 109(Suppl 2), 17200–17207.Google Scholar
38.Therrien, M, Drouin, J. Pituitary pro-opiomelanocortin gene expression requires synergistic interactions of several regulatory elements. Mol Cell Biol. 1991; 11, 3492–3503.Google ScholarPubMed
39.Shin, BC, Dai, Y, Thamotharan, M, Gibson, LC, Devaskar, SU. Pre- and postnatal calorie restriction perturbs early hypothalamic neuropeptide and energy balance. J Neurosci Res. 2012; 90, 1169–1182.Google Scholar
40.Coupe, B, Amarger, V, Grit, I, Benani, A, Parnet, P. Nutritional programming affects hypothalamic organization and early response to leptin. Endocrinol. 2010; 151, 702–713.Google Scholar
41.Fan, C, Liu, X, Shen, W, Deckelbaum, RJ, Qi, K. The regulation of leptin, leptin receptor and pro-opiomelanocortin expression by n-3 PUFAs in diet-induced obese mice is not related to the methylation of their promoters. Nutr Metab. 2011; 8, 31–39.Google Scholar
42.Kouzarides, T. Chromatin modifications and their function. Cell. 2007; 128, 693–705.Google Scholar
43.Li, B, Carey, M, Workman, JL. The role of chromatin during transcription. Cell. 2007; 128, 707–719.Google Scholar
44.Wang, G, Balamotis, MA, Stevens, JL, et al. Mediator requirement for both recruitment and postrecruitment steps in transcription initiation. Mol Cell. 2005; 17, 683–694.CrossRefGoogle ScholarPubMed
45.Pattyn, F, Hoebeeck, J, Robbrecht, P, et al. methBLAST and methPrimerDB: web-tools for PCR based methylation analysis. BMC Bioinformatics. 2006; 7, 496–504.Google Scholar
46.Rajakumar, A, Thamotharan, S, Raychaudhuri, N, Menon, RK, Devaskar, SU. Trans-activators regulating neuronal glucose transporter isoform-3 gene expression in mammalian neurons. J Biol Chem. 2004; 279, 26768–26779.Google Scholar
47.Stevens, A, Begum, G, Cook, A, et al. Epigenetic changes in the hypothalamic proopiomelanocortin and glucocorticoid receptor genes in the ovine fetus after periconceptional undernutrition. Endocrinol. 2010; 151, 3652–3664.Google Scholar
48.Park, JH, Stoffers, DA, Nicholls, RD, Simmons, RA. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest. 2008; 118, 2316–2324.Google Scholar
49.Raychaudhuri, N, Raychaudhuri, S, Thamotharan, M, Devaskar, SU. Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring. J Biol Chem. 2008; 283, 13611–13626.CrossRefGoogle ScholarPubMed
50.Haney, PM, Raefsky-Estrin, C, Caliendo, A, Patel, MS. Precocious induction of hepatic glucokinase and malic enzyme in artificially reared rat pups fed a high-carbohydrate diet. Arch Biochem Biophys. 1986; 244, 787–794.CrossRefGoogle ScholarPubMed