Disorders of food intake, either under consumption by patients with wasting illness or over-consumption in ever-growing rates of obesity, are major health burdens and cost the U.S. billions of dollars in additional health care and lost productivity. Failure to develop effective treatments for these conditions is in large part due to a lack of clear understanding as to how food intake is regulated. Thus, research to explain the processes by which ingestive behavior is controlled is likely to have a major impact on the health of the population. Glucagon-like-peptide-1-(7-36) amide (GLP-1) is an intestinal hormone that has important effects on insulin secretion and glucose metabolism. GLP-1 is also produced in the Central Nervous System (CNS), exclusively in a discrete group of neurons in the caudal brainstem. A single receptor, specific for GLP-1, is expressed in pancreatic beta-cells and by neurons in specific regions of the brain including the hypothalamus, amygdala and caudal brainstem. The neuroanatomical distribution of the central GLP-1 system suggests a role as a relay center for transmitting visceral information to higher centers and there is emerging data indicating that signaling through the central GLP-1 receptor is involved in several aspects of the regulation of food intake. The central hypothesis of this proposal is that signaling through the CNS GLP-1 system is common to the non- homeostatic, meal, and adiposity regulating influences on food intake. The first specific aim will evaluate the hypothesis that signaling through the CNS GLP-1 receptor is a common mechanism through which diverse noxious stimuli activate the response to visceral illness. The second specific aim will use mouse experiments and a conditional genetic targeting system to evaluate the hypothesis that mice with targeted disruption of the GLP-1 receptor develop alternative systems to mediate visceral illness. The third specific aim will evaluate the role of the CNS GLP-1 system in mediating GI-peptide induced satiety. The fourth specific aim will use tissue selective knockouts of the GLP-1 receptor to evaluate the hypothesis that the effects of peripherally administered GLP-1 agonists on body adiposity are mediated by GLP-1r on the pancreatic beta-cell rather than by GLP-1r in the CNS. While overwhelming evidence indicates that GLP-1 can influence food intake, controversy continues to surround the circumstances under which GLP-1 exerts that influence. The execution of the current proposal will result in a more complete understanding of the GLP-1 system and so will add greatly to the overall picture about how food intake and body weight are regulated. This information could lend itself to the development of therapeutic strategies for both wasting conditions as well as obesity.
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