Abstract
The environment can have a long-lasting influence on an individual’s physiology and behavior. While some environmental conditions can be beneficial and result in adaptive responses, others can lead to pathological behaviors (Franklin et al. Neuron 75:747–761, 2012). The period of perinatal development is one of the most critical windows during which adverse conditions can influence the growth and development of the fetus, as well as the offspring’s postnatal health and behavior (Franklin et al. Neuron 75:747–761, 2012). Moreover, recent evidence points to the possibility that changes which occur in the individual can sometimes pass between generations even if the offspring are not directly exposed to the stimulus (Gapp et al. Biology 36:491–502, 2014). Epigenetic alterations are prime candidates for the major molecular mechanism acting at the interface between genetic and environmental factors. Different studies showed that environmental factors, such as fetal alcohol exposure, maternal stress, under or overnutrition, or smoking exposure during sensitive periods affect gene expression in the offspring via altering epigenetic mechanisms, sometimes even across multiple generations (Begum et al. Endocrinology 154:4560–4569, 2013; Blaze and Roth Int J Dev Neurosci 31:804–810, 2013; Laufer et al. Dis Model Mech 6:977–992, 2013; Novakovic et al. Epigenetics 9, 2013). In this review, we discuss the involvement of the proopiomelanocortin (POMC) system, one of the most important regulators of energy balance, and describe how epigenetic changes such as histone modifications and DNA methylation modulate Pomc gene expression and function. We also summarize the recent findings from animal models which show that both diet-induced obesity (DIO) and malnutrition program the POMC system of subsequent generations via epigenetic mechanisms.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Akbarian S, Huang HS (2009) Epigenetic regulation in human brain-focus on histone lysine methylation. Biol Psychiatry 65:198–203
Andersen SL (2003) Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev 27:3–18
Autelitano DJ, Lundblad JR, Blum M, Roberts JL (1989) Hormonal regulation of POMC gene expression. Annu Rev Physiol 51:715–726
Barres R et al (2009) Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab 10:189–198
Barsh GS, Schwartz MW (2002) Genetic approaches to studying energy balance: perception and integration. Nat Rev Genet 3:589–600
Bates SH et al (2003) STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421:856–859
Begum G, Stevens A, Smith EB, Connor K, Challis JR, Bloomfield F, White A (2012) Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning. FASEB J 26:1694–1703
Begum G et al (2013) Maternal undernutrition programs tissue-specific epigenetic changes in the glucocorticoid receptor in adult offspring. Endocrinology 154:4560–4569
Bird A (2007) Perceptions of epigenetics. Nature 447:396–398
Bjorbaek C, Elmquist JK, Michl P, Ahima RS, van Bueren A, McCall AL, Flier JS (1998) Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology 139:3485–3491
Bjorbaek C, El-Haschimi K, Frantz JD, Flier JS (1999) The role of SOCS-3 in leptin signaling and leptin resistance. J Biol Chem 274:30059–30065
Blaze J, Roth TL (2013) Exposure to caregiver maltreatment alters expression levels of epigenetic regulators in the medial prefrontal cortex. Int J Dev Neurosci 31:804–810
Bouret SG, Simerly RB (2006) Developmental programming of hypothalamic feeding circuits. Clin Genet 70:295–301
Burdge GC, Lillycrop KA, Phillips ES, Slater-Jefferies JL, Jackson AA, Hanson MA (2009) Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 139:1054–1060
Campanero MR, Armstrong MI, Flemington EK (2000) CpG methylation as a mechanism for the regulation of E2F activity. Proc Natl Acad Sci U S A 97:6481–6486
Castro MG, Morrison E (1997) Post-translational processing of proopiomelanocortin in the pituitary and in the brain. Crit Rev Neurobiol 11:35–57
Champagne FA, Meaney MJ (2006) Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model. Biol Psychiatry 59:1227–1235
Chiang EP, Wang YC, Chen WW, Tang FY (2009) Effects of insulin and glucose on cellular metabolic fluxes in homocysteine transsulfuration, remethylation, S-adenosylmethionine synthesis, and global deoxyribonucleic acid methylation. J Clin Endocrinol Metab 94:1017–1025
Cho CE, Sanchez-Hernandez D, Reza-Lopez SA, Huot PS, Kim YI, Anderson GH (2013a) High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics 8:710–719
Cho CE, Sanchez-Hernandez D, Reza-Lopez SA, Huot PS, Kim YI, Anderson GH (2013b) Obesogenic phenotype of offspring of dams fed a high multivitamin diet is prevented by a post-weaning high multivitamin or high folate diet. Int J Obes (Lond) 37:1177–1182
Choi J, Li C, McDonald TJ, Comuzzie A, Mattern V, Nathanielsz PW (2011) Emergence of insulin resistance in juvenile baboon offspring of mothers exposed to moderate maternal nutrient reduction. Am J Physiol Regul Integr Comp Physiol 301:R757–R762
Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578
Cone RD et al (1996) The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res 51:287–317, discussion 318
Coupe B, Amarger V, Grit I, Benani A, Parnet P (2010) Nutritional programming affects hypothalamic organization and early response to leptin. Endocrinology 151:702–713
Cowley MA et al (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480–484
Crujeiras AB et al (2013) Association of weight regain with specific methylation levels in the NPY and POMC promoters in leukocytes of obese men: a translational study. Regul Pept 186:1–6
Daskalakis NP, Bagot RC, Parker KJ, Vinkers CH, de Kloet ER (2013) The three-hit concept of vulnerability and resilience: toward understanding adaptation to early-life adversity outcome. Psychoneuroendocrinology 38:1858–1873
Day JJ, Sweatt JD (2012) Epigenetic treatments for cognitive impairments. Neuropsychopharmacology 37:247–260
de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475
Delahaye F et al (2008) Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups. Endocrinology 149:470–475
Dyson MH, Rose S, Mahadevan LC (2001) Acetyllysine-binding and function of bromodomain-containing proteins in chromatin. Front Biosci 6:D853–D865
Eden S et al (2001) An upstream repressor element plays a role in Igf2 imprinting. EMBO J 20:3518–3525
Fan C, Liu X, Shen W, Deckelbaum RJ, Qi K (2011) 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 (Lond) 8:31
Farley C, Cook JA, Spar BD, Austin TM, Kowalski TJ (2003) Meal pattern analysis of diet-induced obesity in susceptible and resistant rats. Obes Res 11:845–851
Finlay BL, Darlington RB (1995) Linked regularities in the development and evolution of mammalian brains. Science 268:1578–1584
Fraga MF, Esteller M (2007) Epigenetics and aging: the targets and the marks. Trends Genet 23:413–418
Franklin TB, Saab BJ, Mansuy IM (2012) Neural mechanisms of stress resilience and vulnerability. Neuron 75:747–761
Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770
Fullston T et al (2013) Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J 27:4226–4243
Funato H, Oda S, Yokofujita J, Igarashi H, Kuroda M (2011) Fasting and high-fat diet alter histone deacetylase expression in the medial hypothalamus. PLoS One 6, e18950
Gao Q, Horvath TL (2008) Cross-talk between estrogen and leptin signaling in the hypothalamus. Am J Physiol Endocrinol Metab 294:E817–E826
Gapp K, von Ziegler L, Tweedie-Cullen RY, Mansuy IM (2014) Early life epigenetic programming and transmission of stress-induced traits in mammals: how and when can environmental factors influence traits and their transgenerational inheritance? BioEssays 36:491–502
Ghildiyal M, Zamore PD (2009) Small silencing RNAs: an expanding universe. Nat Rev Genet 10:94–108
Globisch D et al (2010) Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS One 5, e15367
Goldberg AD, Allis CD, Bernstein E (2007) Epigenetics: a landscape takes shape. Cell 128:635–638
Goll MG et al (2006) Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311:395–398
Gong Y, Ishida-Takahashi R, Villanueva EC, Fingar DC, Munzberg H, Myers MG Jr (2007) The long form of the leptin receptor regulates STAT5 and ribosomal protein S6 via alternate mechanisms. J Biol Chem 282:31019–31027
Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2005) Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat Chem Biol 1:143–145
Gropp E et al (2005) Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci 8:1289–1291
Haberman RP, Quigley CK, Gallagher M (2012) Characterization of CpG island DNA methylation of impairment-related genes in a rat model of cognitive aging. Epigenetics 7:1008–1019
Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD (1991) Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303:1019–1022
Hervouet E, Vallette FM, Cartron PF (2009) Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenetics 4:487–499
Holemans K, Caluwaerts S, Poston L, Van Assche FA (2004) Diet-induced obesity in the rat: a model for gestational diabetes mellitus. Am J Obstet Gynecol 190:858–865
Hsieh J, Gage FH (2005) Chromatin remodeling in neural development and plasticity. Curr Opin Cell Biol 17:664–671
Jeannotte L, Burbach JP, Drouin J (1987) Unusual proopiomelanocortin ribonucleic acids in extrapituitary tissues: intronless transcripts in testes and long poly(a) tails in hypothalamus. Mol Endocrinol 1:749–757
Kellinger MW, Song CX, Chong J, Lu XY, He C, Wang D (2012) 5-formylcytosine and 5-carboxylcytosine reduce the rate and substrate specificity of RNA polymerase II transcription. Nat Struct Mol Biol 19:831–833
Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705
Kuehnen P et al (2012) An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity. PLoS Genet 8, e1002543
Kyle UG, Pichard C (2006) The Dutch famine of 1944–1945: a pathophysiological model of long-term consequences of wasting disease. Curr Opin Clin Nutr Metab Care 9:388–394
Laufer BI, Mantha K, Kleiber ML, Diehl EJ, Addison SM, Singh SM (2013) Long-lasting alterations to DNA methylation and ncRNAs could underlie the effects of fetal alcohol exposure in mice. Dis Model Mech 6:977–992
Levin BE (2006) Metabolic imprinting: critical impact of the perinatal environment on the regulation of energy homeostasis. Philos Trans R Soc Lond B Biol Sci 361:1107–1121
Levin BE, Govek E (1998) Gestational obesity accentuates obesity in obesity-prone progeny. Am J Physiol 275:R1374–R1379
Li C, McDonald TJ, Wu G, Nijland MJ, Nathanielsz PW (2013) Intrauterine growth restriction alters term fetal baboon hypothalamic appetitive peptide balance. J Endocrinol 217:275–282
Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 a resolution. Nature 389:251–260
Lukaszewski MA et al (2013) The hypothalamic POMC mRNA expression is upregulated in prenatally undernourished male rat offspring under high-fat diet. Peptides 43:146–154
Marchesini G, Moscatiello S, Di Domizio S, Forlani G (2008) Obesity-associated liver disease. J Clin Endocrinol Metab 93:S74–S80
Marco A, Kisliouk T, Weller A, Meiri N (2013) High fat diet induces hypermethylation of the hypothalamic Pomc promoter and obesity in post-weaning rats. Psychoneuroendocrinology 38:2844–2853
Marco A, Kisliouk T, Tabachnik T, Meiri N, Weller A (2014) Overweight and CpG methylation of the Pomc promoter in offspring of high-fat-diet-fed dams are not “reprogrammed” by regular chow diet in rats. The FASEB Journal, 28(9):4148–4157
Martin-Gronert MS, Ozanne SE (2013) Early life programming of obesity. Med Wieku Rozwoj 17:7–12
Miranda TB, Jones PA (2007) DNA methylation: the nuts and bolts of repression. J Cell Physiol 213:384–390
Mohan KN, Chaillet JR (2013) Cell and molecular biology of DNA methyltransferase 1. Int Rev Cell Mol Biol 306:1–42
Morris DL, Rui L (2009) Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 297:E1247–E1259
Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD (1994) Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 8:1298–1308
Myers MG Jr, Leibel RL, Seeley RJ, Schwartz MW (2010) Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab 21:643–651
Novakovic B, Ryan J, Pereira N, Boughton B, Craig JM, Saffery R (2014) Postnatal stability and tissue- and time-specific effects of methylation change in response to maternal smoking throughout pregnancy. Epigenetics. 9(3):377–386
Ogden CL, Yanovski SZ, Carroll MD, Flegal KM (2007) The epidemiology of obesity. Gastroenterology 132:2087–2102
Ogden CL, Carroll MD, Kit BK, Flegal KM (2012) Prevalence of obesity in the United States, 2009–2010. NCHS Data Brief (82):1–8
Palou M, Pico C, McKay JA, Sanchez J, Priego T, Mathers JC, Palou A (2011) 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 106:769–778
Pan X, Solomon SS, Borromeo DM, Martinez-Hernandez A, Raghow R (2001) Insulin deprivation leads to deficiency of Sp1 transcription factor in H-411E hepatoma cells and in streptozotocin-induced diabetic ketoacidosis in the rat. Endocrinology 142:1635–1642
Pan H, Guo J, Su Z (2014) Advances in understanding the interrelations between leptin resistance and obesity. Physiol Behav 130C:157–169
Plagemann A et al (2009) Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 587:4963–4976
Plagemann A et al (2010) Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding. J Perinat Med 38:393–400
Poore KR, Fowden AL (2004) The effects of birth weight and postnatal growth patterns on fat depth and plasma leptin concentrations in juvenile and adult pigs. J Physiol 558:295–304
Rudenko A et al (2013) Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79:1109–1122
Sarr O, Yang K, Regnault TR (2012) In utero programming of later adiposity: the role of fetal growth restriction. J Pregnancy 2012:134758
Scharf AN, Imhof A (2011) Every methyl counts—epigenetic calculus. FEBS Lett 585:2001–2007
Schneeberger M, Gomis R, Claret M (2014) Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J Endocrinol 220:T25–T46
Schrauwen P, Westerterp KR (2000) The role of high-fat diets and physical activity in the regulation of body weight. Br J Nutr 84:417–427
Schubeler D (2015) Function and information content of DNA methylation. Nature 517:321–326
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671
Shi X et al (2013) Nuclear factor kappaB (NF-kappaB) suppresses food intake and energy expenditure in mice by directly activating the pomc promoter. Diabetologia 56:925–936
Silverman BL et al (1991) Long-term prospective evaluation of offspring of diabetic mothers. Diabetes 40(Suppl 2):121–125
Smith GP (2000) The controls of eating: a shift from nutritional homeostasis to behavioral neuroscience. Nutrition 16:814–820
Song CX, Yi C, He C (2012) Mapping recently identified nucleotide variants in the genome and transcriptome. Nat Biotechnol 30:1107–1116
Stavropoulos P, Blobel G, Hoelz A (2006) Crystal structure and mechanism of human lysine-specific demethylase-1. Nat Struct Mol Biol 13:626–632
Stevens A et al (2010) Epigenetic changes in the hypothalamic proopiomelanocortin and glucocorticoid receptor genes in the ovine fetus after periconceptional undernutrition. Endocrinology 151:3652–3664
Stocker CJ, Arch JR, Cawthorne MA (2005) Fetal origins of insulin resistance and obesity. Proc Nutr Soc 64:143–151
Sultan FA, Wang J, Tront J, Liebermann DA, Sweatt JD (2012) Genetic deletion of Gadd45b, a regulator of active DNA demethylation, enhances long-term memory and synaptic plasticity. J Neurosci 32:17059–17066
Symonds ME, Sebert SP, Hyatt MA, Budge H (2009) Nutritional programming of the metabolic syndrome. Nat Rev Endocrinol 5:604–610
Szyf M, Bick J (2013) DNA methylation: a mechanism for embedding early life experiences in the genome. Child Dev 84:49–57
Tachibana M, Matsumura Y, Fukuda M, Kimura H, Shinkai Y (2008) G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. EMBO J 27:2681–2690
Tups A (2009) Physiological models of leptin resistance. J Neuroendocrinol 21:961–971
Walley AJ, Blakemore AI, Froguel P (2006) Genetics of obesity and the prediction of risk for health. Hum Mol Genet 15 Spec No 2:R124–R130
Wang X, Lacza Z, Sun YE, Han W (2014) Leptin resistance and obesity in mice with deletion of methyl-CpG-binding protein 2 (MeCP2) in hypothalamic pro-opiomelanocortin (POMC) neurons. Diabetologia 57:236–245
Waterland RA, Garza C (1999) Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr 69:179–197
Waterland RA, Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23:5293–5300
Weller A (2006) The ontogeny of postingestive inhibitory stimuli: examining the role of CCK. Dev Psychobiol 48:368–379
Wu Y, Patchev AV, Daniel G, Almeida OF, Spengler D (2014) Early-life stress reduces DNA methylation of the pomc gene in male mice. Endocrinology 155:1751–1762
Yang G et al (2009) FoxO1 inhibits leptin regulation of pro-opiomelanocortin promoter activity by blocking STAT3 interaction with specificity protein 1. J Biol Chem 284:3719–3727
Youngson NA, Whitelaw E (2008) Transgenerational epigenetic effects. Annu Rev Genomics Hum Genet 9:233–257
Zagoory-Sharon O, Schroeder M, Levine A, Moran TH, Weller A (2008) Adaptation to lactation in OLETF rats lacking CCK-1 receptors: body weight, fat tissues, leptin and oxytocin. Int J Obes (Lond) 32:1211–1221
Zhang X et al (2013) Regulation of estrogen receptor alpha by histone methyltransferase SMYD2-mediated protein methylation. Proc Natl Acad Sci U S A 110:17284–17289
Zhang X et al (2014) Hypermethylation of Sp1 binding site suppresses hypothalamic POMC in neonates and may contribute to metabolic disorders in adults: impact of maternal dietary CLAs. Diabetes 63:1475–1487
Zhu WG et al (2003) Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter. Mol Cell Biol 23:4056–4065
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Marco, A., Weller, A., Meiri, N. (2016). Epigenetic Programming of Hypothalamic Pomc Regulates Feeding and Obesity. In: Spengler, D., Binder, E. (eds) Epigenetics and Neuroendocrinology. Epigenetics and Human Health. Springer, Cham. https://doi.org/10.1007/978-3-319-24493-8_6
Download citation
DOI: https://doi.org/10.1007/978-3-319-24493-8_6
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-24491-4
Online ISBN: 978-3-319-24493-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)