Overnutrition has been consistently identified as a serious health risk by several nutrition/health policy groups including the Food and Nutrition Board of the National Academy of Science, the U. S. Senate Select Committee on Nutrition and Human Needs (Dietary Goals for the United States) and the USDA and DHEW (Nutrition and Your Health: Dietary Guidelines for Americans). The high rate of failure to maintain energy balance has been related to the lack of understanding of the endogenous mechanisms for long-term regulation. Central mechanisms for the control of food intake and the regulation of energy balance are the focus of this proposal. Our main hypothesis is that metabolic activity within specific areas of the brain may be altered to mimic peripheral energy status. In turn these brain areas may utilize this metabolic information to regulate energy balance through control of food intake, endocrine status and autonomic activity. To test this hypothesis, three series of experiments are described. The first series test the main hypothesis directly. The mechanisms of translation of metabolic signals to neurochemical signals is the subject of the second series of experiments. Finally, intervention experiments which test the proposed mechanism are the subject of the third series of experiments. The objectives of the proposal are as follows: 1) To test the hypothesis by directly manipulating hypothalamic metabolic activity and measuring changes in food intake and body composition, 2) To determine the mechanisms by which food intake, energy expenditure or body composition were altered, in situ hybridization measures of neuropeptide mRNA will be made and in vitro release of neuropeptides and neurotransmitters will be measured. The neuropeptides and neurotransmitters known to alter feeding behavior and body composition will be studied, and 3) To determine the mechanisms by which CNS metabolism directly influences the in vitro release of neuropeptides and neurotransmitters. An in vivo approach will be used to validate the in vitro results. Two main approaches will be utilized, antisense- oligonucleotide and the use of specific antibodies. These studies should provide a basic understanding of energy balance regulation and provide the tools for controlling some forms of obesity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD022226-08A1
Application #
2025151
Study Section
Nutrition Study Section (NTN)
Program Officer
Small, Judy A
Project Start
1987-09-30
Project End
2001-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
8
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Georgia
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
City
Athens
State
GA
Country
United States
Zip Code
30602
Wan, H Z; Hulsey, M G; Martin, R J (1998) Intracerebroventricular administration of antisense oligodeoxynucleotide against GLUT2 glucose transporter mRNA reduces food intake, body weight change and glucoprivic feeding response in rats. J Nutr 128:287-91
He, B; White, B D; Edwards, G L et al. (1998) Neuropeptide Y antibody attenuates 2-deoxy-D-glucose induced feeding in rats. Brain Res 781:348-50
He, B; White, B D; Edwards, G L et al. (1998) Longer-term fourth ventricular 5-thioglucose infusion increases body fat in the rat. Proc Soc Exp Biol Med 217:168-72
Sun, M; Martin, R J; Edwards, G L (1997) ICV beta-hydroxybutyrate: effects on food intake, body composition, and body weight in rats. Physiol Behav 61:433-6
Grossman, B M; Devore, M L; Kelso, E W et al. (1997) Effect of glucose and 2-deoxyglucose on hypothalamic GABA release in lactating rats. Physiol Behav 61:169-73
Beverly, J L; Martin, R J (1991) Effect of glucoprivation on glutamate decarboxylase activity in the ventromedial nucleus. Physiol Behav 49:295-9
Millard, W J; Romano, T M; Layden, M P et al. (1991) Growth hormone secretion in the obese male rat: modulation by the gonadal and thyroid axes. Growth Dev Aging 55:91-103
White, B D; Dean, R G; Martin, R J (1990) Adrenalectomy decreases neuropeptide Y mRNA levels in the arcuate nucleus. Brain Res Bull 25:711-5
White, B D; Martin, R J (1990) Alterations in the binding characteristics of glucocorticoid receptors from obese Zucker rats. J Steroid Biochem 36:681-6
Dean, R G; White, B D (1990) Neuropeptide Y expression in rat brain: effects of adrenalectomy. Neurosci Lett 114:339-44

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