Brain Hypothalamic Proopiomelanocortin and High-Fat Diet on Methylation in Offspring as Epigenetic Modifications

  • Jia Zheng
  • Xinhua XiaoEmail author
Reference work entry


Generally, it is believed that genotype and adult lifestyle factors are primary risks of metabolic diseases in life, such as obesity, insulin resistance, and diabetes mellitus. Currently, substantial epidemiological studies and animal experiments indicated maternal overnutrition, such high-fat diet during the critical periods of early life development can significantly increase the predisposition to developing metabolic diseases in later life. However, the underlying mechanism is still not very clear. Recently, epigenetics is hypothesized to be the important molecular basis of the early life overnutrition and abnormal glucose metabolism in adulthood. The fundamental mechanism is that early developmental nutrition can regulate epigenetic modifications of some genes associated with development and metabolism. DNA methylation is the first discovered and an important epigenetic modification. Recent studies suggest that DNA methylation may be the crucial modulators of fetal epigenetic programming in nutrition and metabolic disorders. Furthermore, emerging studies show that brain plays a central role in glucose homeostasis. And the central role of neuropeptides expressed in neurons within nuclei located in the hypothalamus, which can keep balance between food intake and energy expenditure. Most peripheral organs including liver, pancreas, skeletal muscle, and adipose tissue appear to be imprinted by this early imbalanced nutrition. However, investigations into the effects of maternal diet on epigenetic modification of the brain like hypothalamus in the offspring are limited. Therefore, this chapter will focus on brain hypothalamic proopiomelanocortin and high-fat diet on methylation in offspring as epigenetic modifications.


Developmental Origins of Health and Disease (DOHaD) DNA methylation Maternal nutrition High-fat diet Glucose metabolism Diabetes mellitus Obesity Brain Hypothalamic proopiomelanocortin Offspring 

List of Abbreviations


Agouti-related protein


α-melanocyte-stimulating hormone


Cocaine amphetamine–related transcript


Cardiovascular diseases


Developmental Origin of Health and Diseases


Gestational diabetes mellitus


International Diabetes Federation


Melanocortin-4 receptor


Methyl CpG-binding protein 2


μ-opioid receptor


Neuropeptide Y






Type 2 diabetes mellitus






  1. Aguilera O, Fernandez AF, Munoz A, Fraga MF (2010) Epigenetics and environment: a complex relationship. J Appl Physiol 109:243–251CrossRefGoogle Scholar
  2. Berglund ED, Liu T, Kong X, Sohn JW, Vong L, Deng Z, Lee CE, Lee S, Williams KW, Olson DP et al (2014) Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Nat Neurosci 17:911–913CrossRefGoogle Scholar
  3. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21CrossRefGoogle Scholar
  4. Butler AA, Marks DL, Fan W, Kuhn CM, Bartolome M, Cone RD (2001) Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci 4:605–611CrossRefGoogle Scholar
  5. Ceriello A, Testa R, Genovese S (2016) Clinical implications of oxidative stress and potential role of natural antioxidants in diabetic vascular complications. Nutr Metab Cardiovasc Dis 26:285–292CrossRefGoogle Scholar
  6. Chawla A, Chawla R, Jaggi S (2016) Microvasular and macrovascular complications in diabetes mellitus: distinct or continuum? Indian J Endocrinol Metab 20:546–551CrossRefGoogle Scholar
  7. Chen H, Morris MJ (2009) Differential responses of orexigenic neuropeptides to fasting in offspring of obese mothers. Obesity (Silver Spring) 17:1356–1362Google Scholar
  8. Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8:571–578CrossRefGoogle Scholar
  9. Davidowa H, Li Y, Plagemann A (2003) Altered responses to orexigenic (AGRP, MCH) and anorexigenic (alpha-MSH, CART) neuropeptides of paraventricular hypothalamic neurons in early postnatally overfed rats. Eur J Neurosci 18:613–621CrossRefGoogle Scholar
  10. Federation. I.D (2015) IDF Diabetes Atlas, 7th ednGoogle Scholar
  11. Fraga MF (2009) Genetic and epigenetic regulation of aging. Curr Opin Immunol 21:446–453CrossRefGoogle Scholar
  12. Gallou-Kabani C, Gabory A, Tost J, Karimi M, Mayeur S, Lesage J, Boudadi E, Gross MS, Taurelle J, Vige A et al (2010) Sex- and diet-specific changes of imprinted gene expression and DNA methylation in mouse placenta under a high-fat diet. PLoS One 5:e14398CrossRefGoogle Scholar
  13. Gardinergarden M, Frommer M (1987) Cpg islands in vertebrate genomes. J Mol Biol 196:261–282CrossRefGoogle Scholar
  14. Gluckman PD, Hanson MA, Buklijas T, Low FM, Beedle AS (2009) Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol 5:401–408CrossRefGoogle Scholar
  15. Holliday R (2006) Epigenetics a historical overview. Epigenetics 1:76–80CrossRefGoogle Scholar
  16. Holliday R, Pugh JE (1975) DNA modification mechanisms and gene activity during development. Science 187:226–232CrossRefGoogle Scholar
  17. Ibrahim N, Bosch MA, Smart JL, Qiu J, Rubinstein M, Ronnekleiv OK, Low MJ, Kelly MJ (2003) Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology 144:1331–1340CrossRefGoogle Scholar
  18. Ikenasio-Thorpe BA, Breier BH, Vickers MH, Fraser M (2007) Prenatal influences on susceptibility to diet-induced obesity are mediated by altered neuroendocrine gene expression. J Endocrinol 193:31–37CrossRefGoogle Scholar
  19. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33:245–254CrossRefGoogle Scholar
  20. Jang H, Serra C (2014) Nutrition, epigenetics, and diseases. Clin Nutr Res 3:1–8CrossRefGoogle Scholar
  21. Kacem S, Feil R (2009) Chromatin mechanisms in genomic imprinting. Mamm Genome 20:544–556CrossRefGoogle Scholar
  22. Khalyfa A, Carreras A, Hakim F, Cunningham JM, Wang Y, Gozal D (2013) Effects of late gestational high-fat diet on body weight, metabolic regulation and adipokine expression in offspring. Int J Obes 37:1481–1489CrossRefGoogle Scholar
  23. Kulkarni A, Dangat K, Kale A, Sable P, Chavan-Gautam P, Joshi S (2011) Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats. PLoS One 6:e17706CrossRefGoogle Scholar
  24. Lee HS (2015) Impact of maternal diet on the epigenome during in utero life and the developmental programming of diseases in childhood and adulthood. Forum Nutr 7:9492–9507Google Scholar
  25. 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 38:2844–2853CrossRefGoogle Scholar
  26. Marco A, Kisliouk T, Tabachnik T, Weller A, Meiri N (2016) DNA CpG methylation (5-Methylcytosine) and its derivative (5-Hydroxymethylcytosine) alter histone posttranslational modifications at the Pomc promoter, affecting the impact of perinatal diet on leanness and obesity of the offspring. Diabetes 65:2258–2267CrossRefGoogle Scholar
  27. Muhlhausler BS, Adam CL, Findlay PA, Duffield JA, McMillen IC (2006) Increased maternal nutrition alters development of the appetite-regulating network in the brain. FASEB J 20:1257–1259CrossRefGoogle Scholar
  28. Page KC, Malik RE, Ripple JA, Anday EK (2009) Maternal and postweaning diet interaction alters hypothalamic gene expression and modulates response to a high-fat diet in male offspring. Am J Physiol Regul Integr Comp Physiol 297:R1049–R1057CrossRefGoogle Scholar
  29. Patel N, Pasupathy D, Poston L (2015) Determining the consequences of maternal obesity for offspring health. Exp Physiol 100:1421–1428CrossRefGoogle Scholar
  30. Pinhas-Hamiel O, Zeitler P (2005) The global spread of type 2 diabetes mellitus in children and adolescents. J Pediatr 146:693–700CrossRefGoogle Scholar
  31. Pirola L, Balcerczyk A, Okabe J, El-Osta A (2010) Epigenetic phenomena linked to diabetic complications. Nat Rev Endocrinol 6:665–675CrossRefGoogle Scholar
  32. Plagemann A (2005) Perinatal programming and functional teratogenesis: impact on body weight regulation and obesity. Physiol Behav 86:661–668CrossRefGoogle Scholar
  33. Plagemann A, Harder T, Brunn M, Harder A, Roepke K, Wittrock-Staar M, Ziska T, Schellong K, Rodekamp E, Melchior K et al (2009) Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 587:4963–4976CrossRefGoogle Scholar
  34. Rando OJ, Simmons RA (2015) I’m eating for two: parental dietary effects on offspring metabolism. Cell 161:93–105CrossRefGoogle Scholar
  35. Reik W, Dean W (2001) DNA methylation and mammalian epigenetics. Electrophoresis 22:2838–2843CrossRefGoogle Scholar
  36. Roth TL (2012) Epigenetics of neurobiology and behavior during development and adulthood. Dev Psychobiol 54:590–597CrossRefGoogle Scholar
  37. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671CrossRefGoogle Scholar
  38. Skinner MK, Manikkam M, Guerrero-Bosagna C (2010) Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab 21:214–222CrossRefGoogle Scholar
  39. Slatkin M (2009) Epigenetic inheritance and the missing heritability problem. Genetics 182:845–850CrossRefGoogle Scholar
  40. 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 151:3652–3664CrossRefGoogle Scholar
  41. Turner BM (1998) Histone acetylation as an epigenetic determinant of long-term transcriptional competence. Cell Mol Life Sci 54:21–31CrossRefGoogle Scholar
  42. Vogt MC, Bruning JC (2013) CNS insulin signaling in the control of energy homeostasis and glucose metabolism - from embryo to old age. Trends Endocrinol Metab 24:76–84CrossRefGoogle Scholar
  43. Vucetic Z, Kimmel J, Totoki K, Hollenbeck E, Reyes TM (2010) Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology 151:4756–4764CrossRefGoogle Scholar
  44. Vucetic Z, Kimmel J, Reyes TM (2011) Chronic high-fat diet drives postnatal epigenetic regulation of mu-opioid receptor in the brain. Neuropsychopharmacology 36:1199–1206CrossRefGoogle Scholar
  45. Waddington CH (2012) The epigenotype. 1942. Int J Epidemiol 41:10–13CrossRefGoogle Scholar
  46. Warner MJ, Ozanne SE (2010) Mechanisms involved in the developmental programming of adulthood disease. Biochem J 427:333–347CrossRefGoogle Scholar
  47. Watson SJ, Akil H, Richard CW 3rd, Barchas JD (1978) Evidence for two separate opiate peptide neuronal systems. Nature 275:226–228CrossRefGoogle Scholar
  48. Wattez JS, Delahaye F, Lukaszewski MA, Risold PY, Eberle D, Vieau D, Breton C (2013) Perinatal nutrition programs the hypothalamic melanocortin system in offspring. Horm Metab Res 45:980–990CrossRefGoogle Scholar
  49. Zheng J, Xiao X, Zhang Q, Yu M, Xu J, Wang Z, Qi C, Wang T (2015) Maternal and post-weaning high-fat, high-sucrose diet modulates glucose homeostasis and hypothalamic POMC promoter methylation in mouse offspring. Metab Brain Dis 30:1129–1137CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of EndocrinologyPeking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina

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