There is a major epidemic of obesity and type 2 diabetes. Ten-twenty% of this epidemic arises because of in-utero/postnatal malnutrition with subsequent superimposition of western diet and sedentary life style. The undernutrition related factors of fetal/neonatal hypoinsulinemia and hypoleptinemia provoke a cascade of hypothalamic adaptive events, which lend towards a permanency by culminating in hyperphagia/inactivity, visceral adiposity, insulin and leptin resistance. This pro-survival postnatal adaptation targeted at enhancing energy intake and conserving its expenditure consists of an increase in the hypothalamic insulin receptor, leptin receptor expression with an increase in neuropeptide Y, agouti-related peptide expression, and a decrease in melanocortin-3 receptor. Based on these findings, we hypothesize that prenatal/postnatal malnutrition permanently perturbs the hypothalamic 1) leptin &/or insulin receptor and post-receptor signaling pathways, and 2) structure by altering nuclear size, neuronal activity, and feeding neural circuit in the offspring which predates the development of obesity, with 3) a reversal of these alterations with postnatal administration of leptin. To test this hypothesis, we will use the rat model subjected to pre- and postnatal calorie restriction and fed a hypercaloric diet post-weaning.
The specific aims consist of exploring the impact of pre- and post-natal nutrient restriction on male and female p2-suckling, p25-post-suckling, p240-adult, or p450-500-aging adult hypothalamic: I. a) leptin and insulin receptor cross-talk signaling pathways by assessing the ObRb-JAK2-STAT3/SOCS3-SHP2-PTP1B and the IRbeta tyrosine kinase-IRS1/2-P-l-3-kinase- PDK1/2-Akt1/2/PKC;-PDE38-cAMP pathways and b) the orexigenic (NPY/AgRP) and anorexigenic (alpha-MSH) neuropeptides. II. a) nuclear volume assessed by Niss1 staining and quantitative stereology, b) nuclear neuronal activity by using c-fos concentrations, and c) the feeding neural circuitary by retrograde tracking of the neural projections from the arcuate nucleus to the paraventricular, dorsomedial, and lateral hypothalamus. III. a) key leptin and insulin receptor and post-receptor signaling, and b) neuropeptide (NPY/AgRP &alpha-MSH) changes, in response to exogenous administration of systemic leptin between d2 to d7, towards reversal of the ultimate phenotype. The results of our proposed investigations will fill vital gaps in our knowledge and provide the molecular and cellular basis for perinatal nutritional perturbations causing permanent changes in feeding behavior/energy expenditure.
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