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Participation of clock genes in the modulation of secretion and insulin action in malnourished mice

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Author(s):
Patricia Cristine Borck
Total Authors: 1
Document type: Master's Dissertation
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
Defense date:
Examining board members:
Everardo Magalhães Carneiro; José Cipolla Neto; Gabriel Forato Anhê
Advisor: Everardo Magalhães Carneiro
Abstract

The physiological processes such as sleep-wake cycle and metabolism are subject to circadian fluctuations and are regulated by a group of genes known as clock genes or genes clock. Mutations in these genes in mice reduces insulin secretion and ?-pancreatic cell proliferation promoting impaired glucose tolerance and hyperglycemia. Nutritional disorders in the early stages of life are associated with the onset of type 2 diabetes in adulthood. Mice subjected to intrauterine protein restriction have altered expression of clock genes and increased susceptibility to weight gain and glucose intolerance. In this study we aimed to determine the daily expression of clock genes in peripheral tissues, hypothalamus and pancreatic islets of mice subjected to protein restriction. We also evaluated the oscillatory profile of the glucose stimulated insulin secretion and the cholinergic agonist carbachol in this animal model. Mice subjected to protein restriction (R) showed typical features of malnutrition as lower body weight , hypoinsulinemia , hypoproteinemia and increased glucose tolerance and insulin. R mice had higher food consumption, accompanied by changes in the oscillatory profile to Pomc and Npy gene in the hypothalamus. In this tissue, only the expression Rev- erb? gene was influenced by protein restriction. Mice R showed in the liver and muscle loss of the oscillatory profile to Clock and Bmal1 gene. Still, in liver and pancreatic islets the expression of Rev- erb? was changed, with reduction in mRNA content. Regarding the Per1 gene, R mice exhibited advance in the expression of this gene in adipose tissue. In muscle and islets there was loss of daily fluctuation for this gene. R mice exhibited, muscle and adipose tissue, in advance of Per2 gene expression. Islets isolated from control mice (C) showed oscillatory pattern of insulin secretion with the highest levels attained in the ZT 2 e 14 and reduction in the ZT 8. However, R mice had reduced glucose stimulated insulin secretion and loss of its oscillatory profile. R group showed no change in insulin release in the presence of Rev- erb? agonist and antagonist. Furthermore, the expression of Syntaxin, Synaptotagmin, and Insulin genes are reduced in R mice. R group also exhibited oscillatory loss of insulin secretion in the presence of glucose linked Carbachol and the reduction in the expression of Muscarinic Acetylcholine Receptor. With these results we can conclude that mice subjected to protein restriction showed typical features of malnutrition with alterations in glucose homeostasis and insulin secretion. Moreover, R mice exhibited loss of secretion of this hormone profile over 24 hours, which is associated with changes in the expression of Rev- erb?. In addition, there were changes in expression profile of clock genes, especially Rev-erb?, Per1 and Per2 in peripheral tissues, which may be related to changes in glucose tolerance and insulin in R mice (AU)

FAPESP's process: 11/15002-3 - Participation of clock genes in the modulation of insulin secretion in pancreatic islets of malnourished mice
Grantee:Patricia Cristine Borck
Support Opportunities: Scholarships in Brazil - Master