This is a renewal for 5 additional years a grant on the hepatic influences upon feeding. The PI and his colleagues have completed extensive work with the fructose analogue, 2,5-AM. The drug reduces ATP formation in the liver and a signal is relayed to the brain that causes initiation of eating. The PI now proposes to complete the extensive studies necessary to demonstrate that a drug does or does not act in the liver to influence eating with three other antimetabolites: Ouabain, ethionine and mercaptoacetate. In related experiments, labelled drug will be given and the liver, brain, kidneys, epididymal fat and muscle analyzed for uptake. In a second series of proposed experiments, intraportal and intrahepatic infusions of 2,5-AM will be compared with the hepatic branch of the vagus intact or cut. The purpose is to determine if 2,5-AM-elicited eating is caused by hepatic signals travelling in several branches of the vagus or else in several organs in the hepatic bed. A third series of experiments will use two methods, cFOS induction and local cerebral glucose utilization of labelled 2-deoxyglucose, to ascertain which areas of the lower brainstem are activated by 2,5-AM.
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