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Hypothalamic and hippocampal neutral aminopeptidase (APN/CD13), prolyl dipeptidyl aminopeptidase IV (DPPIV/CD26) and C-FOS in monosodium glutamate-treated and food-deprived rats

Grant number: 05/04699-2
Support type:Regular Research Grants
Duration: April 01, 2006 - April 30, 2008
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Paulo Flávio Silveira
Grantee:Paulo Flávio Silveira
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Changes on aminopeptidase (AP) activity levels in certain areas of the central nervous system (CNS) of human narcotic addicts, as well as in rats after morphine withdrawal, or under diabetes mellitus syndrome or water and salt imbalance, have been intriguing findings regarding the present knowledge about the control of food intake and energy balance. In this sense, important phenomena are the unrestricted proteolysis and the relationship among leptin, ghrelin, insulin, glucagon, some neurotransmitter amino acids and many peptides in the CNS, which are susceptible to AP cleavage, mainly in the hypothalamus and hippocampus, such as incretin hormones (bombesin analogs: gastric inhibitory peptide or glucose dependent insulinotropic peptide - GIP, and type 1 and 2 glucagon-like peptides - GLP-1 e GLP-2), neuropeptide Y (NPY), peptide YY (PYY), galanin (GAL), orexin or hypocretin peptides (OX 1 and OX 2 or HCRT 1 and HCRT 2), CART- (cocaine and amphetamine-regulated transcript) peptide, corticotropin-releasing hormone (CRF), thyreotropin-releasing hormone (TRH) and pro-opiomelanocortin (POMC) derived peptides, i.e. melanocortins (adrenocorticotropin - ACTH, and melanocyte-stimulating hormones - MSH - alfa, beta and gama) and beta-endorphins. The objectives of the present project are to determine the pattern of neuronal activation and genic and protein expression, as well as the distribution and catalytic activity of APs related to those aforementioned substrates, i.e. neutral AP (APN)/CD13 (puromycin sensitive and insensitive) and prolyl dipeptidyl AP IV (DPPIV)/CD26, in the hypothalamus and hippocampus of healthy animals, and to recognize changes on these enzymes under food deprivation and in an experimental model of obesity known to present decreased growth hormone (GH) secretion, adiposity, hyperinsulinemia, corticosteronemia and leptinemia, without hyperphagia. This study will be performed in male rats by: (i) induction of obesity through monosodium L-glutamate (MSG) injection; (ii) food deprivation of obese and heathy animals for 72 hours (iii) measurement and comparison of DPPIV and APN activities in soluble (FS) and solubilized membrane-bound (FM) fractions of hypothalamic and hippocampal homogenates from obese animals, from obese animals under food deprivation, from healthy animals (controls) and from healthy animals under food deprivation; (iv) measurement and comparison of genic and protein expression of DPPIV and APN in the hypothalamus and hippocampus of these animals; (v) mapping and comparison of the immunohistochemical distribution of c-fos, CD13 and CD26 in the hypothalamus and hippocampus of these animals. The results from this investigation may contribute to understand the endocrine picture of obesity, eating disorders and cachexia, as well as for searching of new analogs agonists/antagonists of peptide receptors or DPPIV and APN inhibitors, or other options for therapeutic intervention. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ALPONTI, RAFAELA FADONI; FREZZATTI, RODRIGO; BARONE, JULIANA MARTON; ALEGRE, VALTER DE SOUSA; SILVEIRA, PAULO FLAVIO. Dipeptidyl peptidase IV in the hypothalamus and hippocampus of monosodium glutamate obese and food-deprived rats. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 60, n. 2, p. 234-242, FEB 2011. Web of Science Citations: 14.
ALPONTI, RAFAELA FADONI; NOGUEIRA, MARIA INES; MENDES, MARIANA TRIVILIN; DE ABREU, CINTYA; SILVEIRA, PAULO FLAVIO. APM/CD13 and FOS in the hypothalamus of monosodium glutamate obese and food deprived rats. Regulatory Peptides, v. 166, n. 1-3, p. 98-104, JAN 17 2011. Web of Science Citations: 5.
ALPONTI, RAFAELA F.; SILVEIRA, PAULO F. Neutral Aminopeptidase and Dipeptidyl Peptidase IV Activities in Plasma of Monosodium Glutamate Obese and Food-deprived Rats. OBESITY, v. 18, n. 7, p. 1312-1317, JUL 2010. Web of Science Citations: 9.

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