Intrauterine programming of obesity and type 2 diabetes

Fernandez‐Twinn, Denise S.; Hjort, Line; Novakovic, Boris; Ozanne, Susan E.; Saffery, Richard

doi:10.1007/s00125-019-4951-9

Cited by 176 publications

(152 citation statements)

References 125 publications

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“…Accumulating evidence supports that adiposity may be epigenetically regulated and programmed in utero [31][32][33]. However, the biological pathways involved, as well as the influence of the various intrauterine exposures (e.g., maternal obesity and GDM) on epivariations "programming" are yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels

Gagné-Ouellet

Breton

Thibeault

et al. 2020

IJMS

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Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5′-C-phosphate-G-3′ (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother–child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (β = −2.69, p = 0.05) and fat distribution (β = −0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (β = −0.01, p = 0.04) and neonatal leptinemia (β = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood.

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Section: Discussionmentioning

confidence: 99%

Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels

Gagné-Ouellet

Breton

Thibeault

et al. 2020

IJMS

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“…Besides signaling events, various studies have revealed epigenetic mechanisms underlying changes in fetal gene expression in response to an altered intrauterine environment. Such epigenetic mechanisms include DNA methylation and translational repression by miRNAs (reviewed by [35]). In fact, both mechanisms occur in MME regulation: Increased DNA methylation of the MME promoter region was observed in Alzheimer's disease brain [36] and in several types of cancer, such as leukemia [37] and breast cancer [38].…”

Section: Discussionmentioning

confidence: 99%

Maternal Overweight Downregulates MME (Neprilysin) in Feto-Placental Endothelial Cells and in Cord Blood

Weiss

Berger

Brandl

et al. 2020

IJMS

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Maternal overweight in pregnancy alters the metabolic environment and generates chronic low-grade inflammation. This affects fetal development and programs the offspring’s health for developing cardiovascular and metabolic disease later in life. MME (membrane-metalloendopeptidase, neprilysin) cleaves various peptides regulating vascular tone. Endothelial cells express membrane-bound and soluble MME. In adults, the metabolic environment of overweight and obesity upregulates endothelial and circulating MME. We here hypothesized that maternal overweight increases MME in the feto-placental endothelium. We used primary feto-placental endothelial cells (fpEC) isolated from placentas after normal vs. overweight pregnancies and determined MME mRNA, protein, and release. Additionally, soluble cord blood MME was analyzed. The effect of oxygen and tumor necrosis factor α (TNFα) on MME protein in fpEC was investigated in vitro. Maternal overweight reduced MME mRNA (−39.9%, p < 0.05), protein (−42.5%, p = 0.02), and MME release from fpEC (−64.7%, p = 0.02). Both cellular and released MME protein negatively correlated with maternal pre-pregnancy BMI. Similarly, cord blood MME was negatively associated with pre-pregnancy BMI (r = −0.42, p = 0.02). However, hypoxia and TNFα, potential negative regulators of MME expression, did not affect MME protein. Reduction of MME protein in fpEC and in cord blood may alter the balance of vasoactive peptides. Our study highlights the fetal susceptibility to maternal metabolism and inflammatory state.

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“…Epigenetic risk factors The influence of epigenetic risk factors on the development of type 2 diabetes in youth and on cardiometabolic risk across the life span is a rapidly emerging area of research highlighted elsewhere in this special issue by Fernandez-Twinn et al [49] and in other recent reviews [50,51]. In brief, a few themes emerge in the preclinical data that align with clinical data on sex-specific effects of specific epigenetic factors (reviewed in [50][51][52]).…”

Section: Mechanism Of Type 2 Diabetes Onset In Youthmentioning

confidence: 99%

Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course

et al. 2019

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By 2017 estimates, diabetes mellitus affects 425 million people globally; approximately 90-95% of these have type 2 diabetes. This narrative review highlights two domains of sex differences related to the burden of type 2 diabetes across the life span: sex differences in the prevalence and incidence of type 2 diabetes, and sex differences in the cardiovascular burden conferred by type 2 diabetes. In the presence of type 2 diabetes, the difference in the absolute rates of cardiovascular disease (CVD) between men and women lessens, albeit remaining higher in men. Large-scale observational studies suggest that type 2 diabetes confers 25-50% greater excess risk of incident CVD in women compared with men. Physiological and behavioural mechanisms that may underpin both the observed sex differences in the prevalence of type 2 diabetes and the associated cardiovascular burden are discussed in this review. Gender differences in social behavioural norms and disparities in provider-level treatment patterns are also highlighted, but not described in detail. We conclude by discussing research gaps in this area that are worthy of further investigation.

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Intrauterine programming of obesity and type 2 diabetes

Cited by 176 publications

References 125 publications

Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels

Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels

Maternal Overweight Downregulates MME (Neprilysin) in Feto-Placental Endothelial Cells and in Cord Blood

Sex differences in the burden of type 2 diabetes and cardiovascular risk across the life course

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