Dissection of PPAR gama modulation mechanisms as target to treat diabetes and obesity development

• Grant number: 19/14465-1
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2019
• End date: May 31, 2022
• 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). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated researchers: Felipe Rafael Torres ; Fernanda Aparecida Heleno Batista ; Marta García-Arévalo Provencio ; 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 modulation of PPAR³ through post-translational modifications might result in decreasing in its deleterious effects, providing new strategies for insulin sensitization and obesity control. Regarding this, in this project, we intend to uncover the main PPAR³ modulation mechanisms, relating the events of corepressors recruitment and PPAR³ Ser273 phosphorylation or K268 and K293 deacetylation, with the modulation of adipogenesis and insulin resistance. Through structural biology tools (X-ray crystallography, NMR, SAXS), molecular biology assays (cell transactivation, adipogenesis, browning, two-hybrid, reporter gene, qPCR), molecular biology (qPCR and RNAseq) and biophysical techniques (microscale thermophoresis, fluorescence anisotropy), we will provide better knowledge of the mechanistic aspects of relevant interaction interfaces of PPAR³, which are related to metabolic diseases. In addition, we intend to elucidate mechanism in which PPAR³ regulates adipogenesis and browning, together with UCP-1 and Sirt-1, through the development of organoid models that mimic adipose tissue. 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, without producing undesirable side effects. (AU)

Scientific publications

(5)

(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)

BRUNETTI, NATALIA S.; DAVANZO, GUSTAVO G.; DE MORAES, DIOGO; FERRARI, ALLAN J. R.; SOUZA, GABRIELA F.; MURARO, STEFANIE PRIMON; KNITTEL, THIAGO L.; BOLDRINI, VINICIUS O.; MONTEIRO, LAUAR B.; VIRGILIO-DA-SILVA, JOO VICTOR; et al. SARS-CoV-2 uses CD4 to infect T helper lymphocytes. eLIFE, v. 12, p. 26-pg., 2023-07-31. (20/04558-0, 15/15626-8, 19/06459-1, 19/04726-2, 19/16116-4, 19/05155-9, 19/13552-8, 16/18031-8, 19/00098-7, 20/04583-4, 16/00194-8, 21/08354-2, 19/17007-4, 19/22398-2, 17/01184-9, 19/14465-1, 20/04579-7, 13/08293-7, 18/14933-2, 17/23920-9, 19/06372-3, 16/24163-4, 16/23328-0, 20/04919-2, 20/04746-0)

TERRA, MAIARA FERREIRA; GARCIA-AREVALO, MARTA; AVELINO, THAYNA MENDONCA; DEGAKI, KARINA Y.; DE CARVALHO, MURILO; TORRES, FELIPE RAFAEL; SAITO, ANGELA; FIGUEIRA, ANA CAROLINA MIGLIORINI. Obesity-Linked PPAR gamma Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice. BIOMOLECULES, v. 13, n. 4, p. 17-pg., 2023-04-01. (19/14465-1)

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)

GUERRA, JOAO V. S.; DIAS, MARIELI M. G.; BRILHANTE, ANNA J. V. C.; TERRA, MAIARA F.; GARCIA-AREVALO, MARTA; FIGUEIRA, ANA CAROLINA M.. ultifactorial Basis and Therapeutic Strategies in Metabolism-Related Disease. NUTRIENTS, v. 13, n. 8, AUG 2021. (19/14465-1, 19/10274-7)

DE OLIVEIRA, VINICIUS M.; DIAS, MARIELI M. G.; AVELINO, THAYNA M.; VIDEIRA, NATALIA B.; DA SILVA, FERNANDO B.; DORATIOTO, TABATA R.; WHITFORD, PAUL C.; LEITE, VITOR B. P.; FIGUEIRA, ANA CAROLINA M.. pH and the Breast Cancer Recurrent Mutation D538G Affect the Process of Activation of Estrogen Receptor alpha. BIOCHEMISTRY, v. 61, n. 6, p. 9-pg., 2022-02-21. (18/11614-3, 19/10274-7, 14/50739-5, 16/02348-2, 19/22540-3, 16/19766-1, 19/14465-1)