Investigating Ghrelin's Role in Regulating Energy Homeostasis

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Obesity is a major risk factor for many diseases, including, but not limited to, diabetes, cancer, arthritis, high blood pressure and cardiovascular disease. In the United States, roughly 300,000 deaths per year are associated with obesity and overweight. The recent discovery of ghrelin, a peptide found primarily in the stomach with potent stimulatory action on growth hormone release from the pituitary gland, has brought a new understanding of the regulation of energy balance. Ghrelin has been suggested to possess adipogenic, orexigenic and cardiovascular actions that might be independent from its GH stimulatory actions. The overall goal of the proposed research is to clarify the actions of ghrelin on growth and energy homeostasis in vertebrates including humans. Past work by the PIs have isolated ghrelin from the stomach of the tilapia, a euryhaline fish, with a potent GH-releasing activity as in mammals, and has provided preliminary evidence that ghrelin stimulates appetite and body weight gain in the tilapia, which appears to be a result of increased fat deposition. The PIs hypothesize that ghrelin will stimulate the production of fat independent from its GH stimulatory actions. In this proposal the mode of actions of ghrelin on energy homeostasis will be clarified, using CP-477335 (an orally active GH stimulatory compound) and a fish (tilapia) as a model. The specific aims of this proposal are: 1) To investigate whether ghrelin and CP-477335 alter fat deposition, specifically polyunsaturated fatty acids (PUFA), and production of growth factors and their binding proteins in the tilapia. 2) To characterize the actions of ghrelin and CP-477335 on fat deposition, PUFA metabolism and on growth factor production in the liver using culture of primary hepatocytes. The intellectual merit of the proposed studies in its novelty will provide invaluable groundwork for the understanding of ghrelin's actions in directing metabolic investment in vertebrates. To date, there are no reports on the effect of ghrelin on regulating PUFA metabolism in any vertebrate. The proposed studies will provide a comparative approach that will contribute greatly to the knowledge and understanding of how vertebrates partition available metabolic energy, which in turn could be used for the development of biotechnologies applicable to medicine and drugs/treatment associated with pathophysiological conditions.