Obesity and its complications are reaching epidemic proportions in this and other industrialized nations. Women of childbearing age represent a highly affected population, increasing the incidence of acute complications during pregnancy (i.e. preeclampsia and gestational diabetes), as well as long term health consequences in offspring (adult-onset obesity). Given that the perinatal period represents a time of rapid brain development, and that this maturation is sensitive to maternal physiology, these enduring consequences may be caused by stable developmental alterations in brain organization and function. Importantly, studies suggest that leptin (a hormone produced by fat cells that communicates body energy status to the brain) acts as an important factor mediating the correct development of these important weight-regulating circuits. Indeed, leptin administration during this critical perinatal period alters the predisposition to obesity, cardiovascular disease and diabetes later in life in animals exposed to nutritional alterations. In order to understand the role of leptin and leptin signals in the development of hypothalamic neural circuits, we will examine two hypotheses in this application: First, that maternal hyperleptinemia in the absence of obesity will alter the development of projections from hypothalamic arcuate nucleus (ARC) neurons, and that the critical period during which this occurs will be lactation;second, that stable changes to histones and DNA will be induced in offspring of obese mothers that are more susceptible, or more resistant to adult-onset obesity, causing persistent changes in gene expression. We will undertake these studies using mice which over-express leptin to expose offspring to high leptin levels during pregnancy and/or lactation. We will additionally expressing reporter genes in specific populations of cells within the mouse brain, enabling the visualization of neuronal projections from these cells, in addition to examination of expression of genes regulating energy balance. We propose the following specific aims:
Specific Aim 1 : Determine the contribution of maternal leptin concentration during the pre- and postnatal periods on offspring hypothalamic organization and gene expression.
Specific Aim 2 : Characterize distinctive and stable covalent modifications of histones and associated genes in the offspring of diet-induced obese (DIO) mothers that demonstrate resistance, or susceptibility to obesity development. These studies will identify mechanisms regulating the development of neural feeding pathways and link these processes to key developmental periods during which an organism's metabolic fate is shaped. These studies will lay the groundwork for future studies of developmental programming in the predisposition to the metabolic syndrome.
Obesity and its complications are reaching epidemic proportions in this and other industrialized nations. Women of childbearing age represent a highly affected population, increasing the possibility that aspects of maternal obesity may result in developmental and genetic changes in offspring, increasing their risk of metabolic dysfunction as adults. Our proposed research will examine the mechanisms by which offspring brains may be metabolically """"""""programmed"""""""", with the ultimate goal of identifying new targets for the prevention and treatment of obesity.
