Doctoral Dissertations

Date of Award

8-1999

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Psychology

Major Professor

James E. Lawler

Committee Members

Kathleen A. Lawler, Debora Baldwin, Ramin Alemzadeh

Abstract

Neuropeptide Y (NPY) is a powerful stimulant of feeding behavior and metabolic efficiency. Located throughout hypothalamic and extra hypothalamic nuclei, NPY responds to circulating indices of nutritional status like insulin. Obese Zucker rats possess an autosomal recessive trait to become hyperphagic and hyperinsulinemic. Obese Zucker rats also demonstrate chronically elevated levels of NPY throughout the hypothalamus. Some researchers speculate that obese rats possess an insensitive insulin-NPY signaling mechanism resulting in the elevated NPY of these animals. Previous research with the insulin antagonist diazoxide (DZ)demonstrates the drug to be effective at lowering circulating insulin levels of obese rats as well as reducing their food intake and weight gain across the period of treatment. In addition, these peripheral indices of metabolic normalization are accompanied by enhanced levels of insulin in the brain as measured in cerebrospinal fluid. It is possible that the enhanced entry of insulin into the brains of the obese rats causes a reduction in NPY in hypothalamic and extra-hypothalamic nuclei resulting in normalized metabolism and feeding behavior. Thus, the purpose of the current research was to determine if DZ administration across the same time frame that led to enhanced entry of insulin into the brain leads to suppressed hypothalamic and extra-hypothalamic NPY levels. Female lean and obese Zucker rats,approximately six weeks of age, were placed on DZ (150 mg/kg/day) or placebo suspension for about four weeks. Following drug treatment, animals remained free fed or were fasted overnight (12 to 16 hours) before rapid sacrificed by decapitation. Serum was obtained for measurement of insulin and glucose levels, and brains were removed, frozen, and later sliced and punched to obtain the nuclei of interest: ARC, ME, DMH, LH, VMM, PFH,GNA, PVNp, PVNm, AHA, SO, SON, BNST, MPOA, and LPGA. Overnight Fasting lowered insulin of control obese and lean rats, yet lowered glucose only in leans. Fasting also elevated ME and combined ARC-ME and loweredLH NPY levels of obese rats with no effects occurring in leans. DZ treatment reduced weight gain in obese rats only, lowered glucose of both lean and obese rats, but failed to significantly lower insulin of either genotype. Fastingled to more exaggerated effects on NPY than free feeding. DZ elevatedARC, combined ARC-ME, and VMH NPY levels of free fed obese rats, but only elevated LH levels of lean rats. For fasted animals, DZ elevated LH andPFH of obese rats whereas the drug elevated BNST and lowered CNA of lean rats. DZ treatment appears to affect both hypothalamic and extrahypothalamicNPY concentrations of lean and obese Zucker rats. However,the etiology of those changes (e.g., synthesis, release, or transport) remains unknown.

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