There is overwhelming evidence that a signal related to some aspect of energy metabolism is transduced in the liver and used to control food intake. However, it remains to be determined which biochemical event is transduced, how ingested and circulating fuels influence this event, and how the information derived from the liver is integrated with signals from other sites involved in the control of food intake. The project proposed here investigates these questions. The first goal will be to determine the nature of the effective stimulus provided by glucose in the hepatic portal vein. Mechanisms will be identified by comparing the effects of hepatic portal glucose infusions on food intake with (a) the distribution, hepatic uptake, and oxidation of infused glucose, (b) the duration of glucose infusion, and (c) the hepatic glucose gradient (portal-caval difference). The second goal will be to identify the biochemical events in the liver that control food intake. Specific metabolic pathways will be activated or inhibited using novel analogues of fructose. Comparison of behavioral results with in vivo and in vitro physiological measures will determine which metabolic pathways are critical for feeding behavior, and will also test the hypothesis that food intake is controlled by a signal generated by hepatic fuel oxidation. Finally, the hypothesis that fuel oxidation in the liver provides the stimulus for calorie-based conditioning (the acquired oral control of food intake) will be examined by comparing changes in food preference produced by substances that increase or decrease hepatic fuel oxidation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK036339-04
Application #
3234673
Study Section
Biopsychology Study Section (BPO)
Project Start
1986-01-01
Project End
1993-12-31
Budget Start
1989-01-01
Budget End
1989-12-31
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Monell Chemical Senses Center
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Horn, Charles C; Friedman, Mark I (2005) Thoracic cross-over pathways of the rat vagal trunks. Brain Res 1060:153-61
Horn, Charles C; Richardson, Eric J; Andrews, Paul L R et al. (2004) Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anti-cancer agent cisplatin. Auton Neurosci 115:74-81
Horn, Charles C; Ji, Hong; Friedman, Mark I (2004) Etomoxir, a fatty acid oxidation inhibitor, increases food intake and reduces hepatic energy status in rats. Physiol Behav 81:157-62
Horn, Charles C; Friedman, Mark I (2004) Separation of hepatic and gastrointestinal signals from the common ""hepatic"" branch of the vagus. Am J Physiol Regul Integr Comp Physiol 287:R120-6
Horn, Charles C; Friedman, Mark I (2003) Detection of single unit activity from the rat vagus using cluster analysis of principal components. J Neurosci Methods 122:141-7
Horn, C C; Tordoff, M G; Friedman, M I (2001) Role of vagal afferent innervation in feeding and brain Fos expression produced by metabolic inhibitors. Brain Res 919:198-206
Bachmanov, A A; Reed, D R; Tordoff, M G et al. (2001) Nutrient preference and diet-induced adiposity in C57BL/6ByJ and 129P3/J mice. Physiol Behav 72:603-13
Friedman, M I; Harris, R B; Ji, H et al. (1999) Fatty acid oxidation affects food intake by altering hepatic energy status. Am J Physiol 276:R1046-53
Horn, C C; Addis, A; Friedman, M I (1999) Neural substrate for an integrated metabolic control of feeding behavior. Am J Physiol 276:R113-9
Horn, C C; Friedman, M I (1998) Metabolic inhibition increases feeding and brain Fos-like immunoreactivity as a function of diet. Am J Physiol 275:R448-59

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