HIF-1 alpha in metabolic and functional control of adipose tissue resident macrophages in diabetes induced by obesity

• Grant number: 16/18031-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2017
• End date: February 28, 2022
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Gustavo Gastão Davanzo
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 15/15626-8 - Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases, AP.JP
• Associated scholarship(s): 18/24176-4 - Proteomic and metabolomic analysis of adipose tissue macrophages during obesity and insulin resistance: the role of HIF-1a, BE.EP.DR

Abstract

Obesity epidemic affects more people around the world each year, been an important risk factor to type 2 diabetes. With the increase in white adipose tissue (AT), there is a greater migration and infiltration of leucocytes, in which classic M1-like macrophages have a prominent position, they produce pro-inflammatory cytokines, that leads to inflammation in AT and insulin resistance on metabolic tissues. The hypoxia-inducible factor 1 alpha (HIF-1±) has been shown to be an essential regulator to a pro-inflammatory switch in macrophages and regulates the energetic metabolism in these cells, so in hypoxia, as in normóxia. Preliminary data indicates that bone marrow derived macrophages (BMDMs), when stimulated with LPS, show greater production of pro-inflammatory cytokines, glucose transporter 1 (GLUT-1) and enzymes from the glycolytic pathway, with the peak of expression with HIF-1±, as increase in glycolytic rate. In vivo experiments AT resident macrophages (ATM) with M1-like phenotype from obese mice, have shown that they feature greater glycolytic capacity, higher levels of HIF-1± and enhanced expression of HIF-1± target genes and pro-inflammatory cytokines when compared with ATM M1 and M2 of lean mice. Because of that, we consider that HIF-1± expression is responsible for the greater metabolic rate in the initial stages of differentiation of M1-like macrophages, been exacerbated in obesity conditions and sustained by other factors, like aryl hydrocarbon receptor (AHR). So, the main objective of this project is to understand the function of HIF-1± in polarization and metabolic regulation of tissue macrophages. To do so, the project is divided in three parts: (1) culture of BMDMs with or without adipocytes, to analyze the metabolic pathways and activation in different stages of differentiation; (2) analyze the inflammatory and metabolic profile of ATM of lean and obese mice; (3) investigate the role of HIF-1± ATM in obese and insulin resistant animals to compare with lean controls. We will use BMDMs culture and mice WT, Lysmcre, HIF-1±LoxP and with macrophage specific deletion of HIF-1± (MÕhif-1±ko), fed with high fat diet to induce obesity, insulin resistance and low-grade inflammation. The data generated in this project will establish the role of HIF-1± in functional and metabolic modulation of ATM, providing subsidies to better understand the function of these cells in physiological and metabolic contexts, cooperating in the development of new therapeutic approaches. (AU)

Scientific publications

(8)

(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)

DE SOUZA BREDA, CRISTIANE NAFFAH; DAVANZO, GUSTAVO GASTAO; BASSO, PAULO JOSE; SARAIVA CAMARA, NIELS OLSEN; MENDES MORAES-VIEIRA, PEDRO MANOEL. Mitochondria as central hub of the immune system. REDOX BIOLOGY, v. 26, SEP 2019. (15/15626-8, 15/26682-6, 14/10910-7, 17/05264-7, 16/18031-8)

DAVANZO, GUSTAVO GASTAO; CASTRO, GISELE; MORAES-VIEIRA, PEDRO MANOEL M.. Immunometabolic regulation of adipose tissue resident immune cells. CURRENT OPINION IN PHARMACOLOGY, v. 58, p. 44-51, JUN 2021. (19/19435-3, 19/25973-8, 15/15626-8, 16/18031-8)

DAVANZO, GUSTAVO GASTAO; CASTRO, GISELE; MONTEIRO, LAUAR DE BRITO; CASTELUCCI, BIANCA GAZIERI; JACCOMO, VITOR HUGO; SILVA, FELIPE CORREA DA; MARQUES, ANA MARIA; FRANCELIN, CAROLINA; CAMPOS, BRUNA BUENO DE; AGUIAR, CRISTHIANE FAVERO DE; et al. Obesity increases blood-brain barrier permeability and aggravates the mouse model of multiple sclerosis. MULTIPLE SCLEROSIS AND RELATED DISORDERS, v. 72, p. 7-pg., 2023-03-10. (20/16030-0, 15/10107-2, 15/15626-8, 19/25973-8, 16/18031-8)

MONTEIRO, LAUAR DE BRITO; DAVANZO, GUSTAVO GASTAO; DE AGUIAR, CRISTHIANE FAVERO; MORAES-VIEIRA, PEDRO M. M.. Using flow cytometry for mitochondrial assays. METHODSX, v. 7, 2020. (15/15626-8, 16/18031-8)

DA SILVA, FELIPE CORREA; AGUIAR, CRISTHIANE; PEREIRA, JESSICA A. S.; MONTEIRO, LAUAR DE BRITO; DAVANZO, GUSTAVO GASTAO; CODO, ANA CAMPOS; DE FREITAS, LEONARDO PIMENTEL; BERTI, ALINE SIQUEIRA; FERRUCCI, DANILO LOPES; CASTELUCCI, BIANCA GAZIERI; et al. Ghrelin effects on mitochondrial fitness modulates macrophage function. Free Radical Biology and Medicine, v. 145, p. 61-66, DEC 2019. (17/23679-0, 16/18031-8, 17/12848-5, 18/22505-0, 15/15626-8, 17/00079-7, 17/06225-5)

DE FREITAS, LEONARDO PIMENTEL. M-CSF- and L929-derived macrophages present distinct metabolic profiles with similar inflammatory outcomes. Immunobiology, v. 225, n. 3, MAY 2020. (16/18031-8, 15/15626-8, 16/23328-0, 19/06372-3)

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)

CODO, ANA CAMPOS; DAVANZO, GUSTAVO GASTAO; MONTEIRO, LAUAR DE BRITO; DE SOUZA, GABRIELA FABIANO; MURARO, STEFANIE PRIMON; VIRGILIO-DA-SILVA, JOAO VICTOR; PRODONOFF, JULIANA SILVEIRA; CARREGARI, VICTOR CORASOLLA; OLIVEIRA DE BIAGI JUNIOR, CARLOS ALBERTO; CRUNFLI, FERNANDA; et al. Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1 alpha/Glycolysis-Dependent Axis. Cell Metabolism, v. 32, n. 3, p. 15-pg., 2020-09-01. (19/00098-7, 20/04558-0, 20/04522-5, 19/06372-3, 16/18031-8, 15/15626-8, 16/23328-0, 17/01184-9, 20/04919-2, 20/04583-4, 20/04579-7, 18/22505-0, 20/04746-0)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

DAVANZO, Gustavo Gastão. Mechanisms involved in the metabolic regulation of macrophages by the HIF-1alpha transcription factor. 2022. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.