This proposal describes a rigorous and comprehensive plan designed to obtain expert training in advanced MRI
acquisition and analytical methods, developmental systems neuroscience, and fetal programming of health and disease
risk. The proposed research relates to the public health problem of childhood obesity, with a specific focus on the
characterization, role and determinants of energy homeostasis-related brain circuitry in the human newborn. Obesity
is a multi-factorial phenotype. Among these factors, the critical importance of energy homeostasis (balance), and the
hypothalamic-limbic-cortical brain circuitry that regulates it, is well established. However, it is unclear whether the
observed difference in this brain circuitry between obese and normal-weight individuals is a cause or consequence
of the obese state. Also, relatively little is known about the developmental origin (fetal and early postnatal) of variation
in this brain circuitry and its prospective role in shaping propensity for childhood obesity. My proposal addresses
this fundamental knowledge gap. I advance the overarching hypothesis that energy homeostasis brain circuitry a)
already is established by the time of birth; b) exhibits developmental plasticity (fetal programming); and c) is functionally
relevant (predicts postnatal adipose tissue accrual). The K99 mentored phase will be conducted under the
mentorship of leading experts in fetal programming of health and disease (P. Wadhwa), brain imaging (P. Thompson),
and developmental systems neuroscience (D. Fair). I will first develop novel MRI-based measures of the newborn
brain circuitry underlying energy homeostasis, and then identify the prenatal determinants of variation in this
circuitry. The importance of focusing efforts on the newborn brain derives from the logic that brain circuitry at this
time is not yet influenced by postnatal factors. In the R00 phase, I will recruit a new cohort and use a repeated
measures design to address the functional relevance of the initial (newborn) setting of this brain circuitry in the
context of adipose tissue accrual over infancy (a key indicator of childhood obesity risk). K99/Aim 1. Develop
measures of energy homeostasis brain circuitry using anatomical, diffusion and functional MRI. Because such
measures have not yet been established in newborn homeostasis circuitry, this aim will fulfill an important and as
yet unmet need in terms of not only scientific knowledge but also technical capability. K99/Aim 2. Identify the prenatal
(gestational biology) determinants of variation in the measures of newborn brain energy homeostasis circuitry that
are associated with infant adiposity. R00/Aim 3. Address the physiological relevance and clinical significance of these
novel MRI-based newborn brain measures by testing the hypothesis that measures of the human newborn’s energy
homeostasis brain circuitry are prospectively associated with infant adiposity and subsequent childhood obesity
risk. R00/Aim 4. Consider the complimentary hypothesis that infant adiposity at birth is prospectively associated
with changes in newborn energy homeostasis brain circuitry. Significance. By identifying the role and determinants
of energy homeostasis-related brain circuitry in the human newborn, these findings will ultimately provide the basis
for the subsequent development of strategies aimed at the primary prevention of childhood obesity.