This is a request for five additional years support to carry out experiments involving metabolic subcellular changes in the liver and how they influence the onset of meals in rats. Prior evidence produced by the investigator suggests that when food intake is initiated after the administration of the metabolic inhibitor, 2, 5-AM, there are several correlates in hepatocytes that may well have a causal role. More specifically, the results of several types of experiments have converged to strongly implicate that the liver is the target for 2, 5-AMs or exigenicaction; and other experiments have indicated that a key factor (or at least close correlate) is a reduction in the amount of ATP in hepatocytes. Proposed experiments will take the analysis to a more reductionistic level by assessing whether bound or free cellular ATP is more correlated with eating and by then determining if a reduction in the key ATP pool elicit seating when induced by other means; will determine if other drugs thought to elicit eating via the liver (e.g., methyl palmoxirate) are associated with similar hepatocyte changes; will assess the hypothesis that the signal to eat is associated with functioning of the hepatocyte sodium pump; and will determine if changes in hepatocyte calcium pools are a means for generating a signal that could pass from hepatocytes to other cells and on the CNS.
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