Maternal obesity predisposes offspring to metabolic dysfunction and Non-Alcoholic Fatty Liver Disease (NAFLD). Melanocortin-4 receptor (Mc4r)-deficient mouse models exhibit obesity during adulthood. Here, we aim to determine the influence of the Mc4r gene on the liver of mice subjected to perinatal diet-induced obesity. Female mice heterozygous for Mc4r fed an obesogenic or a control diet for 5 weeks were mated with heterozygous males, with the same diet continued throughout pregnancy and lactation, generating four offspring groups: control wild type (C_wt), control knockout (C_KO), obese wild type (Ob_wt), and obese knockout (Ob_KO). At 21 days, offspring were genotyped, weaned onto a control diet, and sacrificed at 6 months old. Offspring phenotypic characteristics, plasma biochemical profile, liver histology, and hepatic gene expression were analyzed. Mc4r_ko offspring showed higher body, liver and adipose tissue weights respect to the wild type animals. Histological examination showed mild hepatic steatosis in offspring group C_KO. The expression of hepatic genes involved in regulating inflammation, fibrosis, and immune cell infiltration were upregulated by the absence of the Mc4r gene. These results demonstrate that maternal obesogenic feeding during the perinatal period programs offspring obesity development with involvement of the Mc4r system.

Center for Translational Medicine International Clinical Research Center Brno 65691 Czech Republic

Department of Gastroenterology and Hepatology Guy's and St Thomas' Hospital NHS Foundation Trust London SE1 7EH UK

Department of Pathology University College London London WC1E 6JJ UK

Division of Women's Health Faculty of Life Sciences and Medicine King's College London London SE1 7EH UK

Institute for Liver and Digestive Health University College London London NW3 2PF UK

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Gonzalez-Muniesa P., Martinez-Gonzalez M.A., Hu F.B., Despres J.P., Matsuzawa Y., Loos R.J.F., Moreno L.A., Bray G.A., Martinez J.A. Obesity. Nat. Rev. Dis. Primers. 2017;3:17034. doi: 10.1038/nrdp.2017.34. PubMed DOI

World Health Organization Obesity and Overweight. [(accessed on 19 July 2017)]; Available online: Http://www.who.int/mediacentre/factsheets/fs311/en/

Fontaine K.R., Redden D.T., Wang C., Westfall A.O., Allison D.B. Years of life lost due to obesity. JAMA. 2003;289:187–193. doi: 10.1001/jama.289.2.187. PubMed DOI

Wang Y.C., McPherson K., Marsh T., Gortmaker S.L., Brown M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011;378:815–825. doi: 10.1016/S0140-6736(11)60814-3. PubMed DOI

Shalitin S., Battelino T., Moreno L.A. Obesity, Metabolic Syndrome and Nutrition. World Rev. Nutr. Diet. 2016;114:21–49. PubMed

Dietrich P., Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Pract. Res. Clin. Gastroenterol. 2014;28:637–653. doi: 10.1016/j.bpg.2014.07.008. PubMed DOI

Temple J.L., Cordero P., Li J., Nguyen V., Oben J.A. A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence. Int. J. Mol. Sci. 2016;17:947. doi: 10.3390/ijms17060947. PubMed DOI PMC

Vinciguerra M. Protein intake, chronic liver diseases, and hepatocellular carcinoma. Hepatology. 2015;61:730. doi: 10.1002/hep.27260. PubMed DOI

Poston L., Caleyachetty R., Cnattingius S., Corvalan C., Uauy R., Herring S., Gillman M.W. Preconceptional and maternal obesity: Epidemiology and health consequences. Lancet Diabetes Endocrinol. 2016;4:1025–1036. doi: 10.1016/S2213-8587(16)30217-0. PubMed DOI

Martinez J.A., Cordero P., Campion J., Milagro F.I. Interplay of early-life nutritional programming on obesity, inflammation and epigenetic outcomes. Proc. Nutr. Soc. 2012;71:276–283. doi: 10.1017/S0029665112000055. PubMed DOI

Mouralidarane A., Soeda J., Sugden D., Bocianowska A., Carter R., Ray S., Saraswati R., Cordero P., Novelli M., Fusai G., et al. Maternal obesity programs offspring Non-Alcoholic Fatty Liver Disease through disruption of 24-h rhythms in mice. Int. J. Obes. 2015;39:1339–1348. doi: 10.1038/ijo.2015.85. PubMed DOI

Oben J.A., Mouralidarane A., Samuelsson A.M., Matthews P.J., Morgan M.L., McKee C., Soeda J., Fernandez-Twinn D.S., Martin-Gronert M.S., Ozanne S.E., et al. Maternal obesity during pregnancy and lactation programs the development of offspring Non-Alcoholic Fatty Liver Disease in mice. J. Hepatol. 2010;52:913–920. doi: 10.1016/j.jhep.2009.12.042. PubMed DOI

Soeda J., Cordero P., Li J., Mouralidarane A., Asilmaz E., Ray S., Nguyen V., Carter R., Novelli M., Vinciguerra M., et al. Hepatic rhythmicity of endoplasmic reticulum stress is disrupted in perinatal and adult mice models of high-fat diet-induced obesity. Int. J. Food Sci. Nutr. 2017;68:455–466. doi: 10.1080/09637486.2016.1261086. PubMed DOI PMC

Pazienza V., Panebianco C., Rappa F., Memoli D., Borghesan M., Cannito S., Oji A., Mazza G., Tamburrino D., Fusai G., et al. Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis. Epigenet. Chromatin. 2016;9:45. doi: 10.1186/s13072-016-0098-9. PubMed DOI PMC

Goni L., Milagro F.I., Cuervo M., Martinez J.A. Single-nucleotide polymorphisms and DNA methylation markers associated with central obesity and regulation of body weight. Nutr. Rev. 2014;72:673–690. doi: 10.1111/nure.12143. PubMed DOI

Loos R.J., Lindgren C.M., Li S., Wheeler E., Zhao J.H., Prokopenko I., Inouye M., Freathy R.M., Attwood A.P., Beckmann J.S., et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 2008;40:768–775. doi: 10.1038/ng.140. PubMed DOI PMC

Xi B., Chandak G.R., Shen Y., Wang Q., Zhou D. Association between common polymorphism near the MC4R gene and obesity risk: A systematic review and meta-analysis. PLoS ONE. 2012;7:e45731. doi: 10.1371/journal.pone.0045731. PubMed DOI PMC

Xi B., Takeuchi F., Chandak G.R., Kato N., Pan H.W., Consortium A.-T.D., Zhou D.H., Pan H.Y., Mi J. Common polymorphism near the MC4R gene is associated with type 2 diabetes: Data from a meta-analysis of 123,373 individuals. Diabetologia. 2012;55:2660–2666. doi: 10.1007/s00125-012-2655-5. PubMed DOI

Krashes M.J., Lowell B.B., Garfield A.S. Melanocortin-4 receptor-regulated energy homeostasis. Nat. Neurosci. 2016;19:206–219. doi: 10.1038/nn.4202. PubMed DOI PMC

Samuelsson A.M. New perspectives on the origin of hypertension; the role of the hypothalamic melanocortin system. Exp. Physiol. 2014;99:1110–1115. doi: 10.1113/expphysiol.2014.080374. PubMed DOI

Tabachnik T., Kisliouk T., Marco A., Meiri N., Weller A. Thyroid Hormone-Dependent Epigenetic Regulation of Melanocortin 4 Receptor Levels in Female Offspring of Obese Rats. Endocrinology. 2017;158:842–851. doi: 10.1210/en.2016-1854. PubMed DOI

Pindjakova J., Sartini C., Lo Re O., Rappa F., Coupe B., Lelouvier B., Pazienza V., Vinciguerra M. Gut Dysbiosis and Adaptive Immune Response in Diet-induced Obesity vs. Systemic Inflammation. Front. Microbiol. 2017;8:1157. doi: 10.3389/fmicb.2017.01157. PubMed DOI PMC

Samuelsson A.S., Mullier A., Maicas N., Oosterhuis N.R., Eun Bae S., Novoselova T.V., Chan L.F., Pombo J.M., Taylor P.D., Joles J.A., et al. Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity. Proc. Natl. Acad. Sci. USA. 2016;113:12298–12303. doi: 10.1073/pnas.1607464113. PubMed DOI PMC

Rappa F., Greco A., Podrini C., Cappello F., Foti M., Bourgoin L., Peyrou M., Marino A., Scibetta N., Williams R., et al. Immunopositivity for histone macroH2A1 isoforms marks steatosis-associated hepatocellular carcinoma. PLoS ONE. 2013;8:e54458. doi: 10.1371/annotation/b456329c-02fa-4055-afb8-2090cec17da6. PubMed DOI PMC

Balthasar N., Dalgaard L.T., Lee C.E., Yu J., Funahashi H., Williams T., Ferreira M., Tang V., McGovern R.A., Kenny C.D., et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 2005;123:493–505. doi: 10.1016/j.cell.2005.08.035. PubMed DOI

Kooijman S., Boon M.R., Parlevliet E.T., Geerling J.J., van de Pol V., Romijn J.A., Havekes L.M., Meurs I., Rensen P.C. Inhibition of the central melanocortin system decreases brown adipose tissue activity. J. Lipid Res. 2014;55:2022–2032. doi: 10.1194/jlr.M045989. PubMed DOI PMC

Barb C.R., Hausman G.J., Rekaya R., Lents C.A., Lkhagvadorj S., Qu L., Cai W., Couture O.P., Anderson L.L., Dekkers J.C., et al. Gene expression in hypothalamus, liver, and adipose tissues and food intake response to melanocortin-4 receptor agonist in pigs expressing melanocortin-4 receptor mutations. Physiol. Genomics. 2010;41:254–268. doi: 10.1152/physiolgenomics.00006.2010. PubMed DOI

Malik I.A., Triebel J., Posselt J., Khan S., Ramadori P., Raddatz D., Ramadori G. Melanocortin receptors in rat liver cells: Change of gene expression and intracellular localization during acute-phase response. Histochem. Cell Biol. 2012;137:279–291. doi: 10.1007/s00418-011-0899-7. PubMed DOI PMC

Xu M., Alwahsh S.M., Ramadori G., Kollmar O., Slotta J.E. Upregulation of hepatic melanocortin 4 receptor during rat liver regeneration. J. Surg. Res. 2016;203:222–230. doi: 10.1016/j.jss.2013.12.019. PubMed DOI

Chambers J.C., Elliott P., Zabaneh D., Zhang W., Li Y., Froguel P., Balding D., Scott J., Kooner J.S. Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat. Genet. 2008;40:716–718. doi: 10.1038/ng.156. PubMed DOI

Itoh M., Suganami T., Nakagawa N., Tanaka M., Yamamoto Y., Kamei Y., Terai S., Sakaida I., Ogawa Y. Melanocortin 4 receptor-deficient mice as a novel Mouse model of nonalcoholic steatohepatitis. Am. J. Pathol. 2011;179:2454–2463. doi: 10.1016/j.ajpath.2011.07.014. PubMed DOI PMC

Soeda J., Mouralidarane A., Cordero P., Li J., Nguyen V., Carter R., Kapur S.R., Pombo J., Poston L., Taylor P.D., et al. Maternal obesity alters endoplasmic reticulum homeostasis in offspring pancreas. J. Physiol. Biochem. 2016;72:281–291. doi: 10.1007/s13105-016-0476-6. PubMed DOI PMC

Mouralidarane A., Soeda J., Visconti-Pugmire C., Samuelsson A.M., Pombo J., Maragkoudaki X., Butt A., Saraswati R., Novelli M., Fusai G., et al. Maternal obesity programs offspring nonalcoholic fatty liver disease by innate immune dysfunction in mice. Hepatology. 2013;58:128–138. doi: 10.1002/hep.26248. PubMed DOI

Nguyen L.T., Saad S., Tan Y., Pollock C., Chen H. Maternal high-fat diet induces metabolic stress response disorders in offspring hypothalamus. J. Mol. Endocrinol. 2017;59:81–92. doi: 10.1530/JME-17-0056. PubMed DOI

Marco A., Kisliouk T., Tabachnik T., Meiri N., Weller A. 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. FASEB J. 2014;28:4148–4157. doi: 10.1096/fj.14-255620. PubMed DOI PMC

Marco A., Kisliouk T., Tabachnik T., Weller A., Meiri N. 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. 2016;65:2258–2267. doi: 10.2337/db15-1608. PubMed DOI

Oben J.A., Patel T., Mouralidarane A., Samuelsson A.M., Matthews P., Pombo J., Morgan M., McKee C., Soeda J., Novelli M., et al. Maternal obesity programmes offspring development of non-alcoholic fatty pancreas disease. Biochem. Biophys. Res. Commun. 2010;394:24–28. doi: 10.1016/j.bbrc.2010.02.057. PubMed DOI PMC