Developmental Programs of Neural Circuits in the Mouse Medial Hypothalamus Neural circuits in the hypothalamus control energy balance by adapting and responding to peripheral signals. However, in humans the high incidence of obesity and insulin resistance associated with Type 2 Diabetes illustrates how metabolic needs are easily uncoupled from appropriate behavioral responses. Identifying factors that modulate the development of these neural circuits may provide novel tools for understanding and controlling human obesity. Using a gene discovery approach we identified ~200 molecular markers that begin to define neuronal subtypes in the neonatal ventromedial hypothalamus (VMH). We hypothesize that eliminating these factors in mice will alter cell fate and compromise normal function of the VMH, some of which are linked to energy homeostasis. To begin testing this hypothesis we will use, or will create mouse model systems. Once produced, we will correlate changes in molecular profiles with phenotypic changes in these mutant mice. We posit that sorting out or classifying VMH neurons according to their molecular signatures will provide the necessary tools to be able to rationally carry out further functional analysis (I.e. electrophysiology). The identification of several novel factors expressed in the neonatal VMH provides an exciting, but significant challenge - namely, how does one choose which of these to study in detail given the cost and time of mouse genetic experiments. In this application we focused on a handful of factors because first, we have obtained floxed mouse lines or the funds to create lines, and second, published data from our lab and others suggests that these factors will be important for VMH development. Our broad approach will be to create different mouse models using a combination of floxed alleles that can be crossed to Cre-Recombinase driver lines. In three aims we will ask how Nkx2.1 and Vgll2 function to specify VMH cell fates, and we will determine how elimination of three SF-1 target genes, Nkx2.2, FezF1 and A2bp1, affects VMH development and function. We will use standard immunohistochemistry, in situ hybridization, and microarray profiling analyses to determine how gene expression and cellular patterns change in different mouse mutants. We will also use SF-1 reporter mice that we have generated;SF-1 positive neurons are labeled with the transneuronal marker, WGA and the Tau-GFP reporter. This approach will be complemented when possible with cellular studies using immortalized hypothalamic cell lines. Limited metabolic and behavioral analysis will be carried out to determine if there are obvious physiological consequences in different mouse mutant lines. In this ambitious and somewhat exploratory application our goal is to begin defining how VMH neuronal subtypes develop and how they are potentially linked to physiology.

Public Health Relevance

Childhood obesity has become one of the major public health concerns for the 21st century and as such, the incidence of Type 2 diabetes is now prevalent in young children. Major advances in the study of body weight regulation have identified central nervous system circuits involving the hypothalamus that controls energy metabolism. Despite this knowledge, the increasing rise in obesity underscores how easily food intake is uncoupled from energy expenditure in our society. It is reasonable to hypothesize that defects disrupting the development of normal neural circuits could predispose an individual to obesity. To begin understanding how these circuits are established a gene discovery approach was undertaken and several new proteins were identified that potentially control hypothalamic development and function. In this application we will begin assessing the role of these new brain markers in the development of neuroendocrine circuits. This application is part of an emerging research area that asks whether early developmental events before or after birth influence the risk of metabolic diseases later in life. Accordingly, results from the proposed studies may provide a new arsenal to combat the growing and costly effects of obesity and Type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Margolis, Ronald N
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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