Hypothalamic Obesity in man and animals is associated with an increase in body fat. The objective of this research proposal is to explore the mechanisms which underlie the development of this type of clinical obesity, using animal models for this purpose. Three major mechanisms have been proposed to explain the development and maintenance of hypothalamic obesity. They are: hyperphagia, hyperinsulinemia, and reduced activity of the sympathetic nervous system. We will explore the role of these mechanisms by using three types of hypothalamic obesity in which these elements can be separated or co-mingled. In weanling rats, a ventromedial hypothalamic lesion increases insulin, reduce sympathetic activity, but does not produce hyperphagia. In rats with PVN-lesions, there is hyperphagia with little evidence for disturbed function of the autonomic nervous system. In adult rats with VMH-lesions, the hyperphagia, hyperinsulinemia and reduced activity of the sympathetic nervous system co-exist. The hypothesis that hyperphagia is an adequate explanation for either of the adult syndromes can be critically addressed by appropriate forms of paired feeding. The possibility that reduced activity alone could induce obesity will be examined in the diabetic weanling rat in which insulin is infused at a constant rate. The role of insulin as a driver of food intake will be tested by infusing insulin either subcutaneously or into the peritoneal space in diabetic adult rats with hypothalamic lesions. The role of insulin as a signal for regulating the plateau which develops during the new steady state after hypothalamic lesions will be studied by raising or lowering insulin in lesioned animals which have reached a plateau weight. Finally, the relationship of the activity of the sympathetic and parasympathetic nervous systems to the plateau state will be assessed by measuring the firing rate of sympathetic nerves to brown adipose tissue and by stimulating the vagal response with injections of insulin into the hypothalamus.
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