Programmed adiposity: genetic in utero and postnatal determinants

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DESCRIPTION (provided by applicant): Early nutritional environment is hypothesized to "program" adult risk for overeating, adiposity, and associated medical complication. However, distinguishing genetic, intrauterine, and postnatal effects has been hampered by the lack of appropriate models. The current application uses a new rodent model that separates "imprinting" effects of early postnatal life on appetite, from genomic and prenatal effects. In Specific Aim 1, behavioral and neurochemical mechanisms by which being reared by an obese dam results in life-long hyperphagia will be studied. Experiments will determine the ontogeny of hyperphagia; the behavioral basis of excess intake, with increased positive drive rather than diminished negative feedback hypothesized to underlies the overeating; and the mediating role of functional neuroadaptations in interrelated systems that subserve the "positive drive" control of feeding, namely neuropeptide Y1, mu/kappa opioid and cannabinoid type 1 receptor systems. The studies combine the following features: 1) highly innovative microstructure analysis of behavior, 2) powerful sibpair split-adoption research designs, 3) detailed dose-response analysis with novel, highly selective pharmacological ligands, 4) recently developed polygenic models of obesity risk, 5) instrumental measures of the reinforcing efficacy of food, and 6) well- matched, controlled diet exposure. In addition, the hormonal and proximate molecular brain mechanisms by which prenatal or postnatal nutritional factors developmentally program adult appetite neurocircuitry are not well understood. Therefore, Specific Aim 2 will determine the effects of postnatal nutrition on early ontogeny of 3 humoral factors - leptin, adiponectin, or corticosterone - hypothesized to program long-term effects of obese adoption on appetite. Laser capture microdissection of discrete hypothalamic nuclei will be combined with microarray analysis to identify genes that are differentially expressed between neonates in relation to postnatal deviations in these "programming" hormones. Microarray analysis also will be used to identify genes that are differentially expressed at birth in the arcuate nucleus in relation to differential genetic or intrauterine overnutrition risk for overeating and obesity in adulthood. The results may identify hormones or hypothalamic genes that program lifelong hyperphagia in developmentally overnourished animals as well as the behavioral and neurochemical mechanisms that proximately mediate the overeating in adulthood.