Synergistic effect of maternal insulin-resistance and cortisol in pregnancy on fetal programming of child mitochondrial function and obesity risk

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Childhood obesity represents a major public health challenge. Growing evidence supports an important role for intrauterine conditions in shaping susceptibility for obesity (the fetal origins concept). However, many key questions remain regarding determinants, outcomes and underlying mechanisms. First, although maternal metabolic and stress hormones have separately been identified as key biological effectors of fetal programming, their interaction has not yet been examined in this context. Second, although it’s well established that it is not BMI, per se, but excess fat mass and its relative distribution (intra-abdominal, hepatic) that underlies the detrimental effects of obesity, it is not yet known whether fetal programming influences the distribution of adipose tissue mass. Third, although mitochondrial function-the central modulator of cellular energy production, storage and use-has been identified as a key mediator of the effects of insulin- resistance (IR) and stress/cortisol on the development and pathogenesis of obesity, its role as a putative mechanism in fetal programming has yet to be determined. Dr. Lauren Gyllenhammer’s K99/R00 proposal addresses these 3 knowledge gaps using complementary designs (observational and experimental), state-of-the-art methods (Magnetic Resonance (MR) and Dual Energy X-Ray Absorptiometry (DXA) imaging), and multiple levels of analysis (cells to in vivo physiology), to test the hypothesis that maternal prenatal stress/cortisol potentiates the unfavorable effects of gestational IR on offspring adipose tissue mass/distribution, mediated by offspring mitochondrial function. In the K99 mentored phase, Dr. Gyllenhammer will leverage and add measures to an ongoing NIH-funded prenatal observational cohort, with existing maternal prenatal cortisol and fasting metabolic measures and offspring serial % fat mass measures (DXA from birth to 5yrs) in N=100 mother/child dyads. She will add novel measures of MR-based adipose tissue distribution and mitochondrial function in the 5 yr old children, and examine the statistical interaction between maternal cortisol and fasting markers of IR on these outcomes. She will advance her knowledge of fetal programming, gestational/developmental biology, and obtain advanced bench and analysis techniques relevant for DOHaD research (cellular biology/mitochondria bench training, bioinformatics analysis methods, cutting-edge MRI methods in newborns and young children) through investigation of these aims, extensive hands-on training, conferences, didactic instruction, and guidance from a diverse advisory committee of respected researchers. In the R00 phase, she will enroll a new, independent cohort of N=80 pregnant women and use an experimental cross-over study design to quantify the physiological interaction of prenatal stress and IR to prospectively predict newborn mitochondrial function and adipose mass and distribution trajectory from birth till 6 mo age. By utilizing training from the K99 phase, she will explore novel cellular mechanisms of prenatal programming, and uncover relationships between maternal prenatal psychological and metabolic stress on offspring adiposity development. Findings from these complementary studies will improve the understanding of early risk factors for child- hood obesity, potentially provide cellular and behavioral interventional targets for prevention and treatment, and will further Dr. Gyllenhammer’s career goal to develop and establish herself as an independent investigator.