PPAR gamma repression mechanism as a target to combat diabetes and obesity

• Grant number: 16/22246-0
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2017
• End date: June 30, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Ana Carolina Migliorini Figueira
• Grantee: Ana Carolina Migliorini Figueira
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Campinas , SP, Brazil
• Associated researchers: Albane Coirier le Maire ; Fernanda Aparecida Heleno Batista ; Paulo Sergio Lopes de Oliveira

Abstract

Obesity and type 2 diabetes are chronic diseases characterized by increased body fat and insulin resistance. The growing number of new cases per year have been considered alarming and, for this reason, the development of new therapies has considerable importance. In this scenario, nuclear receptors play fundamental roles, being important modulation targets. The PPAR³ is one of these targets, acting effectively in adipogenesis and insulin sensitization. Diverse studies point that repression of PPAR³ or the modulation of its phosphorylation might result in decreasing of its deleterious effects, providing new strategies for insulin sensitization control. Regarding this, in this project, we intend to uncover the main repression mechanisms of PPAR³, relating the events of corepressors recruitment and PPAR³ Ser273 phosphorylation, with the modulation of adipogenesis and insulin resistance. Through structural biology tools (X-ray crystallography, NMR, SAXS), molecular biology assays (cell transactivation, two-hybrid, reporter gene, qPCR), biophysical techniques (microscale thermophoresis, fluorescence anisotropy, FRET) and quantitative characterization of PPAR³/CoR interaction in cells, we will provide better knowledge of the mechanistic aspects of relevant interaction interfaces of PPAR³, which are related to metabolic diseases. The set of obtained results will be extremely important to provide relevant information on the mechanism of action of this receptor, and to generate new targets for drug development targeting the PPAR³ repression, without producing undesirable side effects. (AU)

Scientific publications

(6)

(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)

DIAS, MARIELI MARIANO GONCALVES; BATISTA, FERNANDA APARECIDA HELENO; TITTANEGRO, THAIS HELENA; DE OLIVEIRA, ANDRE GUSTAVO; LE MAIRE, ALBANE; TORRES, FELIPE RAFAEL; FILHO, HELDER VERAS RIBEIRO; SILVEIRA, LEONARDO REIS; FIGUEIRA, ANA CAROLINA MIGLIORINI. PPAR gamma S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment. FRONTIERS IN ENDOCRINOLOGY, v. 11, NOV 27 2020. (19/14465-1, 16/13480-9, 16/22246-0)

RIBEIRO FILHO, V, H.; GUERRA, V, J.; CAGLIARI, R.; BATISTA, F. A. H.; LE MAIRE, A.; OLIVEIRA, P. S. L.; FIGUEIRA, A. C. M.. Exploring the mechanism of PPAR gamma phosphorylation mediated by CDK5. Journal of Structural Biology, v. 207, n. 3, p. 317-326, SEP 1 2019. (16/22246-0)

DE GUZZI CASSAGO, CAROLINA APARECIDA; DIAS, MARILIA MEIRA; PINHEIRO, MATHEUS PINTO; PASQUALI, CAMILA CRISTINA; SILVA BASTOS, ALLINY CRISTINY; ISLAM, ZEYAUL; CONSONNI, SILVIO ROBERTO; DE OLIVEIRA, JULIANA FERREIRA; GOMES, EMERSON MACHI; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; et al. Glutaminase Affects the Transcriptional Activity of Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma) via Direct Interaction. BIOCHEMISTRY, v. 57, n. 44, p. 6293-6307, NOV 6 2018. (14/20673-2, 11/10127-2, 17/11766-5, 16/22246-0, 15/25832-4, 10/13992-3, 14/19518-2, 11/13981-4)

CAMPOS, JESSICA L. O.; DORATIOTO, TABATA R.; VIDEIRA, NATALIA B.; RIBEIRO FILHO, V, HELDER; BATISTA, FERNANDA A. H.; FATTORI, JULIANA; INDOLFO, NATHALIA DE C.; NAKAHIRA, MARCEL; BAJGELMAN, MARCIO C.; CVORO, ALEKSANDRA; et al. Protein Disulfide Isomerase Modulates the Activation of Thyroid Hormone Receptors. FRONTIERS IN ENDOCRINOLOGY, v. 9, JAN 8 2019. (16/22246-0, 13/07937-8, 11/23659-2, 13/08743-2, 14/22215-1)

RIBEIRO FILHO, HELDER VERAS; VIDEIRA, NATALIA BERNARDI; BRIDI, ALINE VILLANOVA; TITTANEGRO, THAIS HELENA; HELENA BATISTA, FERNANDA APARECIDA; DE CARVALHO PEREIRA, JOSE GERALDO; LOPES DE OLIVEIRA, PAULO SERGIO; BAJGELMAN, MARCIO CHAIM; LE MAIRE, ALBANE; MIGLIORINI FIGUEIRA, ANA CAROLINA. Screening for PPAR Non-Agonist Ligands Followed by Characterization of a Hit, AM-879, with Additional No-Adipogenic and cdk5-Mediated Phosphorylation Inhibition Properties. FRONTIERS IN ENDOCRINOLOGY, v. 9, FEB 1 2018. (16/22246-0, 13/26507-4)

RIBEIRO FILHO, HELDER VERAS; TAMBONES, IZABELLA LUISA; GONCALVES DIAS, MARIELI MARIANO; VIDEIRA, NATALIA BERNARDI; BRUDER, MARJORIE; AMATO, ANGELICA AMORIM; MIGLIORINI FIGUEIRA, ANA CAROLINA. Modulation of nuclear receptor function: Targeting the protein-DNA interface. Molecular and Cellular Endocrinology, v. 484, p. 1-14, MAR 15 2019. (16/22246-0, 18/02481-0)