Role of physical exercise in the regulation of MKP-3 protein in hypothalamic of obese mammals: effects on insulin signaling

Author(s)

Bárbara de Almeida Rodrigues

• Document type: Doctoral Thesis
• Press: Limeira, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Aplicadas
• Defense date: 2017-10-26

Examining board members

José Rodrigo Pauli; André Ricardo Gomes de Proença; Vania D'Almeida; Leandro Fernandes; Maria Cláudia Gonçalves de Oliveira

• Advisor: Leandro Pereira de Moura; José Rodrigo Pauli

Abstract

The insulin action in the hypothalamus is crucial for the food intake control. On fed state the insulin is secreted and reaches the hypothalamus which phosphorylates and extracts the FoxO1 protein (transcription factor of the forkhead BOX O family) of the nucleus, decreasing the transcription of orexigenic neuropeptides (NPY, neuropeptide Y, and peptide related to the agouti gene, AgRP). Conversely, when there is impairment in the insulin transduction signal the FoxO1 remains in the nucleus of the neuronal cells, elevating the synthesis of orexigenic neuripeptides ,taking to the increased hunger. In this context, the MAPK-phosphatase-3 (MKP-3) protein has the ability to dephosphorylate FoxO1, remaining in the nucleus, inducing increase of NPY and AgRP in the hypothalamus and consequently causing hyperphagia and increase of adipose body mass. Therefore, therapeutic actions capable of having an inhibitory effect on MKP-3 in neuronal cells of the hypothalamus can be shown as important agents against obesity and comorbidities. The objective of the present study was to verify the physical exercise effects on the MKP-3 protein content and insulin signaling in the obese mice hypothalamus induced by diet rich in saturated fat. Swiss mice were distributed in groups : control, fed with a standard ration for rodents, obese (OB), fed with high fat diet diet and obeses exercised acutely (OBEXE). After analysis of body composition and food intake, were indentified the proteins of interest of the insulin signaling cascade through the Western Blot technique. Assays were also performed with HEK293 cells in Swiss control mice with or not adenovirus administration to overexpress MKP-3 and to evaluate the effects on food intake and phosphorylation of the FoxO1. To identify the MKP-3 phosphatase action on FoxO1 dephosphorylation, we used HEK293 cells treated or not with insulin and an adenoviral vector of MKP-3 and GFP (control) injected intracerebroventricular (icv) in mice. After the treatments the molecular analyzes were done through the Westen Blot technique. It is verified through the results that obesity increased the proteic content of MKP-3 in the hypothalamus and this was accompanied by an increase of food intake and body adiposity of the camundongos. The adenoviruses experiments showed that the overexpression of MKP-3 causes FoxO1 dephosphorylation and impairment on hunger control stimulated by insulin. However, an increase in physical exercise was observed on the hypothalamic MKP-3 protein. We conclude that the obesity condition is associated with an increase in MKP-3 levels in the hypothalamus and this is associated with hyperphagia. Physical exercise was not able to inhibit the activity of this protein on desfoforilar the FoxO1 transcriptional factor in the hypothalamus. Capable Interventions of inhibiting the MKP-3 can become relevant strategies on the obesity treatment (AU)

• FAPESP's process: 13/25512-4 - Role of physical exercise in the regulation of MKP-3 protein in the hypothalamus of obese rats: effects on insulin signaling.
• Grantee: Barbara de Almeida Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate