It is proposed to investigate four interrelated areas concerning cyclo-(His-Pro) (C(HP)) and appetite regulation. The long range goal is to understand how C(HP) causes appetite suppression and to achieve long-term appetite suppression in the rat and primate. 1. To characterize how and where C(HP) exerts its appetite suppressive actions in the hypothalamus, its effects upon fasting- and refeeding-associated alterations in the content and turnover of catecholamines will be investigated by HPLC. Stereospecific receptors for 3H-C(HP) in the hypothalamus will be sought and their relevance to appetite control examined. To understand the mechanism of the acute elevations in hypothalamic C(HP) concentrations, transcription rates of the preproTRH (preproC(HP)) genome will be studied using a 32P-cDNA probe for pro-TRH. The ultrastructural co-localization of C(HP) in hypothalamic nuclei will be studied with light and electron microscopic immunocytochemistry. 2. Potential mechanisms underlying the fluctuations in small bowel C(HP) concentrations with fasting and feeding will be examined by studying the synthesis, secretion, and turnover rate of C(HP) in relation to nutrient status. The ultrastructural features of the small bowel C(HP) will be characterized to determine whether C(HP) is in neural or endocrine structures. 3. The potential role of C(HP) in the pathophysiology of experimental obesity will be investigated in rodent models of acquired and hereditary obesity. 4. Long-term appetite suppression and weight loss in both rats and primates will be accomplished by administration of C(HP) either intraventricularly, subcutaneously, or orally.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK037378-03
Application #
3236251
Study Section
Endocrinology Study Section (END)
Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1989-09-01
Budget End
1990-03-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Wilber, J F (1991) Neuropeptides, appetite regulation, and human obesity. JAMA 266:257-9
Yamada, M; Wilber, J F (1990) Reciprocal regulation of preprothyrotropin-releasing hormone (TRH) mRNA in the rat anterior hypothalamus by thyroid hormone: dissociation from TRH concentrations during hypothyroidism. Neuropeptides 15:49-53
Hilton, C W; Prasad, C; Wilber, J F (1990) Acute alterations of cyclo(His-Pro) levels after oral ingestion of glucose. Neuropeptides 15:55-9
Yamada, M; Radovick, S; Wondisford, F E et al. (1990) Cloning and structure of human genomic DNA and hypothalamic cDNA encoding human prepro thyrotropin-releasing hormone. Mol Endocrinol 4:551-6
Hilton, C W; Reddy, S; Prasad, C et al. (1990) Change in circulating cyclo(His-Pro) concentrations in rats after ingestion of oral glucose compared to intravenous glucose and controls. Endocr Res 16:139-50
Hilton, C W; Wolf, G C; Wilber, J F et al. (1989) Identification and characterization of cyclo(His-Pro)-like immunoreactivity in amniotic fluid. Peptides 10:299-301
Yamada, M; Rogers, D; Wilber, J F (1989) Exogenous triiodothyronine lowers thyrotropin-releasing hormone concentrations in the specific hypothalamic nucleus (paraventricular) involved in thyrotropin regulation and also in posterior nucleus. Neuroendocrinology 50:560-3
Ikegami, H; Spahn, S A; Prasad, C (1989) Neuropeptide-dopamine interactions. IV. Effect of thyrotropin-releasing hormone on striatal dopaminergic neurons. Peptides 10:681-5
Hilton, C W; Prasad, C; Wilber, J F et al. (1989) Radioimmunoassay of cyclo(His-Pro) in unextracted human plasma: report of a normal range and definition of factors critical for successful assay. Neuropeptides 13:65-70
Yamada, M; Wilber, J F (1989) The distribution of histidyl-proline diketopiperazine [cyclo(His-Pro)] in discrete rat hypothalamic nuclei. Neuropeptides 13:221-3

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