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.
