Altered food intake is a fundamental component of the adaptive response to changing energy demands. One of the most striking examples of this phenomenon is the marked increase of food intake (hyperphagia) induced by uncontrolled insulin-dependent diabetes mellitus, both in animal models and in man. Although widely perceived to result from impaired glucose metabolism or its sequelae, the applicant proposes that diabetic hyperphagia results from a deficiency of insulin in the central nervous system (CNS). This hypothesis is supported by studies which suggest that the entry of circulating insulin to the brain plays a major role in body weight regulation, and that an important component of this action is to suppress food intake. Accordingly, insulin-deficient states, such as untreated diabetes and food deprivation, cause a marked increase of food intake. Recent work by the applicant suggests that one consequence of low levels of insulin in the CNS is to increase hypothalamic biosynthesis of neuropeptide Y (NPY), a potent stimulant of food intake. Expression of the NPY gene by neurons of the hypothalamic arcuate nucleus, an area rich in insulin receptors, is increased in both food-deprived and uncontrolled diabetic animals, and in both conditions, increased NPY biosynthesis is inhibited by administration of insulin directly into the brain. The applicant therefore hypothesizes that the induction of CNS insulin deficiency by conditions such as fasting or diabetes stimulates hypothalamic NPY gene expression, which leads to hyperphagic feeding.
The aim of this proposal is to use the model of diabetic hyperphagia as a tool to investigate the role of insulin and its interaction with hypothalamic neuropeptides in the control of food intake. By quantifying hypothalamic neuropeptide gene expression using the methods of in situ hybridization and radioimmunoassay (to determine neuropeptide mRNA and peptide levels, respectively) and by altering levels of insulin and NPY within the hypothalamus using both intracerebroventricular and intrahypothalamic infusion techniques, studies in this application propose to l) infuse insulin into the brain of diabetic rats at doses which do not alter peripheral manifestations of diabetes in order to quantify the extent to which CNS insulin deficiency underlies the increased hypothalamic NPY gene expression and hyperphagia characteristic of the diabetic state; 2) administer antibodies specific to NPY into the CNS of diabetic rats to assess whether increased NPY release is responsible for diabetic hyperphagia; 3) administer antibodies specific to insulin into the hypothalamus of normal, nondiabetic rats to determine if CNS insulin deficiency induced by this method causes hyperphagia via an increase in hypothalamic NPY biosynthesis; and 4) determine the effect of diabetes and CNS insulin deficiency to alter hypothalamic expression of other neuropeptides involved in feeding (galanin, corticotrophin releasing hormone, and cholecystokinin). In addition to providing insight into altered feeding behavior in diabetic animals, these studies will help clarify basic mechanisms underlying regulation of feeding behavior and body weight. This information will be useful not only to the study of human diabetes, but to disorders such as obesity as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS032273-05
Application #
2771940
Study Section
Biopsychology Study Section (BPO)
Program Officer
Kitt, Cheryl A
Project Start
1994-09-01
Project End
1999-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Williams, Diana L; Baskin, Denis G; Schwartz, Michael W (2009) Hindbrain leptin receptor stimulation enhances the anorexic response to cholecystokinin. Am J Physiol Regul Integr Comp Physiol 297:R1238-46
Sarruf, David A; Yu, Fang; Nguyen, Hong T et al. (2009) Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology 150:707-12