Advertisement

Maternal obesity and gestational diabetes are associated with placental leptin DNA methylation

      Objective

      In this study, we aimed to investigate relationships between maternal prepregnancy obesity and gestational diabetes mellitus and placental leptin DNA methylation.

      Study Design

      This study comprises data on 535 mother-infant dyads enrolled in the Rhode Island Child Health Study, a prospective cohort study of healthy term pregnancies. Prepregnancy body mass index was calculated from self-reported anthropometric measures and gestational diabetes mellitus diagnoses gathered from inpatient medical records. DNA methylation of the leptin promoter region was assessed in placental tissue collected at birth using quantitative bisulfite pyrosequencing.

      Results

      In a multivariable regression analysis adjusted for confounders, infants exposed to gestational diabetes mellitus had higher placental leptin methylation (β = 1.89, P = .04), as did those demonstrating prepregnancy obesity (β = 1.17, P = .06). Using a structural equations model, we observed that gestational diabetes mellitus is a mediator of the effects of prepregnancy obesity on placental leptin DNA methylation (β = 0.81, 95% confidence interval, 0.27–2.71).

      Conclusion

      Our results suggest that the maternal metabolic status before and during pregnancy can alter placental DNA methylation profile at birth and potentially contribute to metabolic programming of obesity and related conditions.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Simmons D.
        Diabetes and obesity in pregnancy.
        Best Pract Res Clin Obstet Gynaecol. 2011; 25: 25-36
        • Gluckman P.D.
        • Hanson M.A.
        • Pinal C.
        The developmental origins of adult disease.
        Matern Child Nutr. 2005; 1: 130-141
        • Zambrano E.
        • Nathanielsz P.W.
        Mechanisms by which maternal obesity programs offspring for obesity: evidence from animal studies.
        Nutr Rev. 2013; 71: S42-S54
        • Waterland R.A.
        • Michels K.B.
        Epigenetic epidemiology of the developmental origins hypothesis.
        Annu Rev Nutr. 2007; 27: 363-388
        • Jaenisch R.
        • Bird A.
        Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.
        Nat Genet. 2003; 33: 245-254
        • Ruchat S.-M.
        • Hivert M.-F.
        • Bouchard L.
        Epigenetic programming of obesity and diabetes by in utero exposure to gestational diabetes mellitus.
        Nutr Rev. 2013; 71: S88-S94
        • Burton G.J.
        • Barker D.J.
        • Moffett A.
        • Thornburg K.
        The placenta and human developmental programming.
        Cambridge University Press, Cambridge (United Kingdom)2010
        • Tessier D.
        • Ferraro Z.
        • Gruslin A.
        Role of leptin in pregnancy: consequences of maternal obesity.
        Placenta. 2013; 34: 205-211
        • Bouchard L.
        • Thibault S.
        • Guay S.P.
        • et al.
        Leptin gene epigenetic adaptation to impaired glucose metabolism during pregnancy.
        Diabetes Care. 2010; 33: 2436-2441
        • Lesseur C.
        • Armstrong D.A.
        • Murphy M.A.
        • et al.
        Sex-specific associations between placental leptin promoter DNA methylation and infant neurobehavior.
        Psychoneuroendocrinology. 2014; 40: 1-9
        • Melzner I.
        • Scott V.
        • Dorsch K.
        • et al.
        Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoter.
        J Biol Chem. 2002; 277: 45420-45427
        • Noer A.
        • Sorensen A.L.
        • Boquest A.C.
        • Collas P.
        Stable CpG hypomethylation of adipogenic promoters in freshly isolated, cultured, and differentiated mesenchymal stem cells from adipose tissue.
        Mol Biol Cell. 2006; 17: 3543-3556
        • Marchi M.
        • Lisi S.
        • Curcio M.
        • et al.
        Human leptin tissue distribution, but not weight loss-dependent change in expression, is associated with methylation of its promoter.
        Epigenetics. 2011; 6: 1198-1206
        • Vickers M.H.
        • Sloboda D.M.
        Leptin as mediator of the effects of developmental programming.
        Best Pract Res Clin Endocrinol Metab. 2012; 26: 677-687
        • Seki Y.
        • Williams L.
        • Vuguin P.M.
        • Charron M.J.
        Minireview: epigenetic programming of diabetes and obesity: animal models.
        Endocrinology. 2012; 153: 1031-1038
        • Jousse C.
        • Parry L.
        • Lambert-Langlais S.
        • et al.
        Perinatal undernutrition affects the methylation and expression of the leptin gene in adults: implication for the understanding of metabolic syndrome.
        FASEB J. 2011; 25: 3271-3278
        • Tobi E.W.
        • Lumey L.H.
        • Talens R.P.
        • et al.
        DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific.
        Hum Mol Genet. 2009; 18: 4046-4053
        • Filiberto A.C.
        • Maccani M.A.
        • Koestler D.
        • et al.
        Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta.
        Epigenetics. 2011; 6: 566-572
        • Fenton T.
        A new growth chart for preterm babies: Babson and Benda’s chart updated with recent data and a new format.
        BMC Pediatr. 2003; 3: 13
        • Armstrong D.A.
        • Lesseur C.
        • Conradt E.
        • Lester B.M.
        • Marsit C.J.
        Global and gene-specific DNA methylation across multiple tissues in early infancy: implications for children’s health research.
        FASEB J. 2014; 28: 2088-2097
        • Fenton T.R.
        • Kim J.H.
        A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants.
        BMC Pediatr. 2013; 13: 59
        • Rasmussen K.M.
        • Abrams B.
        • Bodnar L.M.
        • Butte N.F.
        • Catalano P.M.
        • Siega-Riz A.M.
        Recommendations for weight gain during pregnancy in the context of the obesity epidemic.
        Obstet Gynecol. 2010; 116: 1191-1195
        • Shrout P.E.
        • Bolger N.
        Mediation in experimental and nonexperimental studies: new procedures and recommendations.
        Psychol Methods. 2002; 7: 422
        • Soubry A.
        • Murphy S.K.
        • Wang F.
        • et al.
        Newborns of obese parents have altered DNA methylation patterns at imprinted genes.
        Int J Obes. 2013; https://doi.org/10.1038/ijo.2013.193
        • Gemma C.
        • Sookoian S.
        • Alvarinas J.
        • et al.
        Maternal pregestational BMI is associated with methylation of the PPARGC1A promoter in newborns.
        Obesity. 2009; 17: 1032-1039
        • Farley D.M.
        • Choi J.
        • Dudley D.J.
        • et al.
        Placental amino acid transport and placental leptin resistance in pregnancies complicated by maternal obesity.
        Placenta. 2010; 31: 718-724
        • Misra V.K.
        • Trudeau S.
        The influence of overweight and obesity on longitudinal trends in maternal serum leptin levels during pregnancy.
        Obesity. 2011; 19: 416-421
        • Saben J.
        • Lindsey F.
        • Zhong Y.
        • et al.
        Maternal obesity is associated with a lipotoxic placental environment.
        Placenta. 2014; 35: 171-177
        • El Hajj N.
        • Pliushch G.
        • Schneider E.
        • et al.
        Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus.
        Diabetes. 2013; 62: 1320-1328
        • Lesseur C.
        • Armstrong D.A.
        • Paquette A.G.
        • Koestler D.C.
        • Padbury J.F.
        • Marsit C.J.
        Tissue-specific Leptin promoter DNA methylation is associated with maternal and infant perinatal factors.
        Mol Cell Endocrinol. 2013; 381: 160-167
        • Clifton V.L.
        Review: sex and the human placenta: mediating differential strategies of fetal growth and survival.
        Placenta. 2010; 31: S33-S39
        • Kleiblova P.
        • Dostalova I.
        • Bartlova M.
        • et al.
        Expression of adipokines and estrogen receptors in adipose tissue and placenta of patients with gestational diabetes mellitus.
        Mol Cell Endocrinol. 2010; 314: 150-156
        • Lappas M.
        • Permezel M.
        • Rice G.E.
        Leptin and adiponectin stimulate the release of proinflammatory cytokines and prostaglandins from human placenta and maternal adipose tissue via nuclear factor-kappaB, peroxisomal proliferator-activated receptor-gamma and extracellularly regulated kinase 1/2.
        Endocrinology. 2005; 146: 3334-3342
        • Catalano P.M.
        Obesity, insulin resistance, and pregnancy outcome.
        Reproduction. 2010; 140: 365-371
        • Pirkola J.
        • Pouta A.
        • Bloigu A.
        • et al.
        Risks of overweight and abdominal obesity at age 16 years associated with prenatal exposures to maternal prepregnancy overweight and gestational diabetes mellitus.
        Diabetes Care. 2010; 33: 1115-1121
        • Aiken C.E.
        • Ozanne S.E.
        Sex differences in developmental programming models.
        Reproduction. 2013; 145: R1-R13
        • Baptiste-Roberts K.
        Maternal obesity and implications for the long-term health of the offspring.
        in: Obesity during pregnancy in clinical practice. Springer, London2014: 259-295