Dorsomedial Hypothalamic Signaling Pathways and Energy Balance

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DESCRIPTION (provided by applicant): The hypothalamus plays a central role in maintaining energy homeostasis. Within the hypothalamus, different nuclei have been shown to play distinct roles in controlling food intake and energy expenditure. Although a role for the dorsomedial hypothalamus (DMH) in feeding and body weight controls has long been suggested from data demonstrating that DMH lesions result in decreases in food intake, body weight and linear growth, the neural mechanisms underlying the effects of DMH lesions or the basic contributions of this nucleus to overall energy homeostasis remain to be discerned. The long-term goal of this proposal is to characterize DMH signaling pathways and identify how DMH peptide signaling affects food intake and body weight. The proposed experiments focus on the actions of DMH neuropeptide Y (NPY) and corticotrophin releasing factor (CRF). The focus on NPY is based on the observations that DMH NPY is overexpressed in a variety of states such as lactation, chronic food restriction, and exercise, and is elevated in a number of obesity syndromes. The focus on CRF derives from our recent data demonstrating that DMH CRF expression is induced or up-regulated in exercise-induced anorexia. We hypothesize that DMH NPY, under the control of brain CCK, and that DMH CRF, potentially under the control of melanocortin signaling, provide the main functional orexigenic and anorexigenic outputs of the DMH. We propose two Specific Aims. In the first Specific Aim, we will characterize the actions of CCK on DMH NPY neuronal signaling and identify pathways that mediate the actions of DMH NPY in the control of food intake and body weight by using in situ hybridization, c-Fos like immunohistochemstry and Fluorogold retrograde tracing techniques. We will also identify DMH NPY functions in energy balance control by altering DMH NPY expression with adeno- associated virus (AAV)-induced overexpression or RNA interference. In the second Specific Aim, we will assess the potential relationships of hypothalamic melanocortin and/or NPY signaling system(s) with DMH CRF neural signaling and examine the role of DMH CRF in feeding control by assessing the effects of site- specific AAV-mediated CRF RNA interference. Overall, the elucidation of the actions of these DMH peptide systems in feeding and body weight control would significantly advance our understanding of the role of this hypothalamic nucleus in maintaining energy homeostasis.