Early Life Fatty Acid Exposures Dictate Obesity Predisposition

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Project Summary and Abstract This application is a resubmission for the K01 Career Development Award mentored by Dr. Paul MacLean and co-mentored by Dr. Jacob Friedman at the University of Colorado Anschutz Medical Campus School of Medicine. This proposal focuses on elucidating mechanisms established by postnatal fatty acid nutrition that control adipose development in the neonate. The study design uncouples effects of postnatal nutrition (milk fatty acids) from fetal fatty acid exposures, and the milk n-6/n-3 PUFA ratio exposures in the young will be manipulated using a well-characterized transgenic mouse, combined with a basic cross-fostering approach. My overarching hypothesis is that postnatal exposure to high n-6/n-3 PUFA hypomethylates DNA of adipogenic pathways, which persists into adulthood to confer adipocyte-intrinsic obesity predisposition. Lowering the postnatal milk PUFA ratio will reverse postnatal programming, improving metabolic health later in life. I have integrated my comprehensive training plan with the two novel approaches designed to test specific effects of postnatal milk PUFA ratio on neonatal adipose development and function: Postnatal milk n-6/n-3 PUFA ∆ % DNA methylation in Adipocyte Precursors ∆ Adipose Function AIM1. Determine the effect of postnatal dietary PUFA ratio on the adipogenic potential of adipocyte precursor cells. AIM2. Determine how altered neonatal dietary PUFA affects adipose tissue development and function. I will address gaps in my training by adding targeted didactic and technical skills development, including high- throughput sequencing analysis, NIDDK tracers workshop, and adipocyte biology workshops, as well as skills with flow cytometry, DNA methylation, isotope tracers, and metabolic phenotyping. I have recruited a team of highly productive leaders in the fields of adipose biology and pediatric obesity research, including my mentor Dr. MacLean and co-mentor Dr. Friedman, adipocyte precursor biology (Drs. Klemm and Rodeheffer), epigenetics and computational biology (Drs. Yang and Jones), and in mass spectrometry of isotopes and lipid (Dr. Murphy). This training plan encompasses cutting edge epigenetic analytical tools, an outstanding network of advisors with considerably expertise, and an innovative experimental approach that facilitate a successful transition to an independent career as an academic scientist in the developmental origins of obesity.