Recent advances in the physiology of energy homeostasis provide a well-defined and testable model for understanding how uncontrolled insulin-deficient diabetes mellitus affects feeding behavior. This model is based on the hypothesis that negative feedback control of body adiposity involves the hormones, insulin and leptin, that circulate at concentrations proportional to body fat content. These hormones are hypothesized to reduce food intake and body weight by acting upon discrete hypothalamic signaling systems, referred to here as """"""""central effector pathways."""""""" The effect of weight loss induced by uncontrolled diabetes to lower circulating levels of insulin and leptin is thus proposed to cause diabetic hyperphagia. This response is hypothesized to result in part via activation of hypothalamic neurons that co-express neuropeptide Y (NPY) and an endogenous melanocortin receptor antagonist, known as """"""""Agouti-related protein"""""""" (Agrp) (both of which stimulate food intake), and by the inhibition of neurons that contain melanocortins (which reduce food intake). The objectives of this application are 1) to determine the importance of leptin deficiency as a mediator of the effect of uncontrolled diabetes on these hypothalamic neurons. This will be accomplished by infusing leptin systemically at a dose that precisely replaces the physiological leptin level in diabetic mice that are leptin-deficient, and by measuring hypothalamic expression of these neuropeptide mRNAs by in situ hybridization; 2) To use mice with genetic NPY deficiency to test the hypothesis that NPY is required for the hyperphagic response to diabetes; 3) To determine whether glucocorticoid hormones act in combination with insulin and leptin to regulate hypothalamic neuropeptide gene expression in diabetic rats; and 4) to determine if uncontrolled diabetes activates other hypothalamic neuropeptide systems implicated in the control of food intake, such as pathways containing melanin concentrating hormone and the orexins, and whether changing levels of glucocorticoids, leptin or insulin mediate these responses. These studies will 1) improve our understanding of a behavioral disorder commonly encountered among patients with diabetes, and 2) help to clarify the interactions between hormones involved in energy homeostasis and the targets upon which they act.
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