Postabsorptive fuel metabolism is an important factor in the control of food intake. Sensors in brain and liver that are sensitive to various metabolic parameters have been implicated in this control. In liver, considerable evidence indicates that changes in energy metabolism produce a stimulus or stimuli that are transduced into a neural signal that carries this metabolic information to the central nervous system for use in controlling food intake. In particular, changes in hepatic ATP content, or some closely related change in liver energy status, generate signals that initiate or terminate feeding behavior under various conditions, such as fasting-refeeding, type I diabetes, and treatment with metabolic inhibitors. Recent studies in this laboratory have revealed that three different animal models of obesity (genetic, dietary and neurological) show reduced hepatic energy status, suggesting that changes in liver energy status are also involved in overeating and the development of obesity. The overall goal of this project is to assess whether and how altered hepatic energy metabolism is a contributing cause of hyperphagia (overeating) that leads to obesity. Some rats overeat and become obese when fed a diet high in fat content (obesity-prone), whereas others of the same strain do not (obesity-resistant). The proposed research will use this diet-induced animal model of obesity because it appears most comparable to the obesity commonly seen in humans. We hypothesize that, during the development of obesity, hyperphagia may be driven at least in part by decreased liver energy status, which is secondary to the redirection of fuels into storage and away from oxidative pathways. Overeating could result from a faster decline in hepatic energy status between meals or a slower recovery in hepatic energy status during and after a meal. The project has three specific aims: (1) Determine whether overeating in obesity prone rats is due to an enhanced susceptibility to reductions in liver energy status. (2) Determine whether overeating in obesity prone rats is due to a slow restoration of liver energy status. (3) Determine whether calcium signaling during metabolic stimulus transduction differs in hepatocytes from lean and obese rats. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053109-11
Application #
6857093
Study Section
Nutrition Study Section (NTN)
Program Officer
Yanovski, Susan Z
Project Start
1993-08-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2007-03-31
Support Year
11
Fiscal Year
2005
Total Cost
$312,597
Indirect Cost
Name
Monell Chemical Senses Center
Department
Type
DUNS #
088812565
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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