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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053109-07
Application #
6124828
Study Section
Special Emphasis Panel (ZRG2-BPO (02))
Program Officer
Yanovski, Susan Z
Project Start
1993-08-01
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
7
Fiscal Year
2000
Total Cost
$274,293
Indirect Cost
Name
Monell Chemical Senses Center
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ji, H; Friedman, M I (2008) Reduced hepatocyte fatty acid oxidation in outbred rats prescreened for susceptibility to diet-induced obesity. Int J Obes (Lond) 32:1331-4
Ji, Hong; Friedman, Mark I (2007) Reduced capacity for fatty acid oxidation in rats with inherited susceptibility to diet-induced obesity. Metabolism 56:1124-30
Friedman, Mark I (2007) Obesity and the hepatic control of feeding behavior. Drug News Perspect 20:573-8
Stefan, M; Ji, H; Simmons, R A et al. (2005) Hormonal and metabolic defects in a prader-willi syndrome mouse model with neonatal failure to thrive. Endocrinology 146:4377-85
Ji, Hong; Outterbridge, Lisa V; Friedman, Mark I (2005) Phenotype-based treatment of dietary obesity: differential effects of fenofibrate in obesity-prone and obesity-resistant rats. Metabolism 54:421-9
Friedman, Mark I; Graczyk-Millbrandt, Grazyna; Ji, Hong et al. (2003) 2,5-Anhydro-D-mannitol increases hepatocyte sodium: transduction of a hepatic hunger stimulus? Biochim Biophys Acta 1642:53-8
Ji, Hong; Friedman, Mark I (2003) Fasting plasma triglyceride levels and fat oxidation predict dietary obesity in rats. Physiol Behav 78:767-72
Rawson, Nancy E; Ji, Hong; Friedman, Mark I (2003) 2,5-Anhydro-D-mannitol increases hepatocyte calcium: implications for a hepatic hunger stimulus. Biochim Biophys Acta 1642:59-66
Friedman, Mark I; Koch, James E; Graczyk-Milbrandt, Grazyna et al. (2002) High-fat diet prevents eating response and attenuates liver ATP decline in rats given 2,5-anhydro-D-mannitol. Am J Physiol Regul Integr Comp Physiol 282:R710-4
Ji, Hong; Graczyk-Milbrandt, Grazyna; Osbakken, Mary D et al. (2002) Interactions of dietary fat and 2,5-anhydro-D-mannitol on energy metabolism in isolated rat hepatocytes. Am J Physiol Regul Integr Comp Physiol 282:R715-20

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