Abstract
BackgroundLeptin, mainly secreted by fat cells, plays a core role in the regulation of appetite and body weight, and has been proposed as a mediator of metabolic programming. During pregnancy leptin is also secreted by the placenta, as well as being a key regulatory cytokine for the development, homeostatic regulation and nutrient transport within the placenta. South Asians have a high burden of type 2 diabetes, partly attributed to a “thin-fat-phenotype”.ObjectiveOur aim was to investigate how maternal ethnicity, adiposity and glucose- and lipid/cholesterol levels in pregnancy are related to placental leptin gene (LEP) DNA methylation.MethodsWe performed DNA methylation analyses of 13 placental LEP CpG sites in 40 ethnic Europeans and 40 ethnic South Asians participating in the STORK-Groruddalen cohort.ResultsSouth Asian ethnicity and gestational diabetes (GDM) were associated with higher placental LEP methylation. The largest ethnic difference was found for CpG11 [5.8% (95% CI: 2.4, 9.2), p<0.001], and the strongest associations with GDM was seen for CpG5 [5.2% (1.4, 9.0), p=0.008]. Higher maternal LDL-cholesterol was associated with lower placental LEP methylation, in particular for CpG11 [-3.6% (-5.5, -1.4) per one mmol/L increase in LDL, p<0.001]. After adjustments, including for nutritional factors involved in the one-carbon-metabolism cycle (vitamin D, B12 and folate levels), ethnic differences in placental LEP methylation were strongly attenuated, while associations with glucose and LDL-cholesterol persisted.ConclusionsMaternal glucose and lipid metabolism is related to placental LEP methylation, whilst metabolic and nutritional factors largely explain a higher methylation level among ethnic South Asians.
Highlights
Leptin, mainly secreted by fat cells, plays a core role in the regulation of appetite and body weight, and has been proposed as a mediator of metabolic programming
Eligible for the present study were ethnic Western European and South Asian mothers participating in the STORK-Groruddalen cohort, with singleton pregnancies, gestational age ≥35 weeks and a valid weight at birth, a macroscopic placenta examination performed, and data regarding GDM from an oral glucose tolerance test (OGTT), offered to all study participants (Figure S1, Flow chart)
We found that South Asian ethnic origin and maternal GDM were associated with higher placental leptin gene (LEP) methylation, while higher low-density lipoprotein (LDL)-cholesterol was associated with lower LEP methylation
Summary
Mainly secreted by fat cells, plays a core role in the regulation of appetite and body weight, and has been proposed as a mediator of metabolic programming. During pregnancy leptin is secreted by the placenta, as well as being a key regulatory cytokine for the development, homeostatic regulation and nutrient transport within the placenta. Physiological changes in maternal body composition and glucose and lipid metabolism occur to ensure appropriate supply of nutrients to the growing fetus [1]. Glucose is the major nutrient required for fetal growth and is primarily sourced from the maternal circulation and transported across placenta by facilitated diffusion [1]. Triglycerides are hydrolysed by lipases on the maternal side of the placental syncytiotrophoblast, and free fatty acids are released and taken up by the placenta. Cholesterol is probably mainly delivered to the placenta by LDL-cholesterol, taken up by endocytosis [3]
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