The long term objective of this research is to gain an understanding of the neural pathways and cellular mechanisms that are involved in the metabolic regulation of energy expenditure thereby providing therapeutic targets for increasing energy expenditure and combating obesity. The proposed research plan is a comprehensive, logically-organized, hypothesis-driven series of studies to examine a novel mechanism for a fundamental regulation of energy expenditure (decreased sympathetic activation of brown adipose tissue in situations of decreased fuel availability) that may contribute to the inability to lose body weight by caloric restriction. This model is especially relevant since new data demonstrate brown adipose tissue in adult humans and both clinical and non-human studies demonstrate that the functional amount of this tissue is inversely correlated with obesity. The proposed studies will utilize functional neuroanatomical and in vivo electrophysiological techniques to elucidate the organization and pharmacology of the neural pathway responsible for the glucoprivation or fasting-induced decrease in sympathetic activation of brown adipose tissue. The three specific aims will test clearly defined hypotheses on the functional roles of specific neurochemically-defined neurons in the ventrolateral medulla, the paraventricular nucleus of the hypothalamus, and the raphe pallidus area in the glucoprivation-induced decrease in energy expenditure in brown adipose tissue. Understanding the neural pathways and mechanisms that inhibit sympathetic outflow to brown adipose tissue will provide a foundation for determining how alterations in these pathways contribute to overweight and obesity, and will represent an important step towards the development of therapeutic approaches to increase energy expenditure even in the face of dietary restriction and thereby combat obesity.
Energy expenditure is an important neurally regulated component of energy homeostasis. Alterations in energy homeostasis (imbalances between energy intake and energy expenditure) can result in body weight gain and contribute to the growing epidemic of obesity, which is associated with increased risk for diabetes, heart disease, hypertension, and cancer. The knowledge of the neural circuits and neurotransmitters involved in the sympathetic regulation of energy expenditure that will be gained from the proposed studies will suggest targets for therapeutic approaches to increase energy expenditure and thereby combat obesity.
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