Testing the fuel-mediated hypothesis: maternal insulin resistance and glucose mediate the association between maternal and neonatal adiposity, the Healthy Start study

Abstract

Aims/hypothesis In women who are overweight or obese before or during pregnancy there is an associated risk of increased fetal growth and higher birthweight. The metabolic phenotype of the overweight/obese pregnant woman, characterised by higher than normal insulin resistance (IR) and increased circulating fuels, suggests a mechanism resulting in fetal overnutrition and subsequent increased adiposity. We tested the fuel-mediated hypothesis in an observational pre-birth cohort of 951 mother–offspring pairs, the Healthy Start study. Methods We conducted a path analysis to estimate the simultaneous effects of maternal IR and maternal fuels (fasting glucose, triacylglycerol [TG] and NEFA levels) in late pregnancy in mediating the relationship between maternal pre-pregnancy BMI and neonatal adiposity (per cent fat mass [%FM]). Results The total effect of maternal BMI on neonatal %FM was significant (total effect 0.16, 95% CI 0.08, 0.22, p < 0.001). The mediated path including maternal IR and glucose levels together accounted for 21% (p < 0.01) of the total effect of maternal BMI on neonatal %FM while the mediating effects of all other fuels were non-significant. Conclusions/interpretation Using a novel application of path analysis our data implicate maternal IR and glucose levels as important mediators of the association between maternal and infant adiposity.

Maternal obesity and offspring body composition by indirect methods: a systematic review and meta-analysis

“…Ten studies were conducted in the United States 5,6,29,30,32,33,34,35,36,37 , two in the United Kingdom 28,38 , two in Denmark 32,39 , one in Australia 27 , one in Brazil 31 , and one in Portugal 40 ( Table 1). The number of participants in the cohorts ranged from 78 34 to 3,263 38 .…”

“…Eight studies measured body composition in newborns 5,6,27,29,32,33,37,40 , whilst all other studies measured body composition in childhood (2-11 years of age). The methods for the assessment of body composition included DEXA in eight studies 28,30,32,34,35,36,38,39 , ADP in seven 5,6,27,31,33,37,38 and TOBEC in one 29 (Table 2). …”

“…13 reported fat mass 5,6,29,30,31,32,33,34,35,37,38,39,40 and two FMI 28,31 as the primary outcome. In nine studies 5,28,29,31,32,33,34,35,38 univariate analyses showed a statistically significant positive association between maternal pre-pregnancy BMI and fat mass in offspring. This association remained significant after adjusting for confounders in six of the studies 28,29,31,32,34,38 .…”

Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism

“…No mother had clinical evidence of insulin resistance, and none had preeclampsia. Maternal and infant phenotypes in the larger population have been previously described (24,26).…”

“…The Healthy Start Study at the University of Colorado (ClinicalTrials.gov; NCT02273297) is a longitudinal prospective observational prebirth cohort of 1,400 maternal-infant pairs beginning in early pregnancy that has revealed important associations between maternal phenotype and infant adiposity at birth (24,26). To investigate the Biology of intraUterine Metabolic Programming (BUMP), umbilical cord tissue was obtained at birth from a convenience sample of 165 Healthy Start infants and used to culture uMSC as an ancillary part of the Healthy Start Study (Baby BUMP Project).…”