Study of the metabolic regulation of macrophages by leptin

• Grant number: 16/23328-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2017
• End date: March 31, 2021
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Lauar de Brito Monteiro
• 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): 18/19338-5 - The study of the metabolic and functional modulation of macrophages by leptin, BE.EP.DD

Abstract

Obesity-induced inflammation is a risk factor for several acute and chronic pathologies. Investigating how metabolism can affect the immune response and how obesity, by affecting the systemic metabolism, modulates metabolism and cellular immune function will provide new mechanisms for understanding immunemetabolic regulation under different physiological and pathological conditions. Central player regulating this metabolic crosstalk includes leptin, an adipokine produced by the adipose tissue that participates in controlling food consumption and is present in high cocentrations in obese individuals. The role of leptin as a pro-inflammatory adipokine is well established. Animals lacking leptin or its receptor present numerous metabolic and immunologic changes, however the role of leptin signaling in the metabolic control of immune cell subtypes, such as macrophages, is not yet established. Thus, this proposal hypothesizes that leptin will regulate differently in lean and obese animals the metabolism of tissue macrophages and, cosequently, their immune function. The main goal is to understand how leptin modulates macrophage metabolism and function under both physiological and pathological (obesity) conditions. OBRLoxp mice will be crossed with LysMcre to conditionally knockout leptin receptor in myeloid cells, among them macrophages. The metabolism and functional polarization of macrophages will be studied in vitro and in vivo. Transgenic mice will be fed a high fat diet to induce obesity, insulin resistance and low-grade systemic inflammation. The inflammatory and metabolic statuses of adipose tissue resident macrophages from diet-induced obese mice will be determined and compared to lean control mice. Our preliminary results indicate that leptin potentiates the induction of glycolysis in macrophages stimulated with LPS. Thereby, we expect that leptin will promote increased glycolysis and M1 polarization in adipose tissue resident macrophage through the differential activation of mTOR, being this potentiated in obesity. The interactions between multiple levels in the metabolic and immune systems suggest pathogenic mechanisms that might underlie many of the complications observed in obesisty and may provide novel therapeutic applications. (AU)

Scientific publications

(7)

(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)

MONTEIRO, LAUAR; DA SILVA PEREIRA, JESSICA APARECIDA; PALHINHA, LOHANNA; MORAES-VIEIRA, PEDRO MANOEL M.. Leptin in the regulation of the immunometabolism of adipose tissue-macrophages. Journal of Leukocyte Biology, v. 106, n. 3, SI, p. 703-716, SEP 2019. (15/15626-8, 16/23328-0, 17/00079-7)

MONTEIRO, LAUAR DE BRITO; PRODONOFF, JULIANA SILVEIRA; DE AGUIAR, CRISTHIANE FAVERO; CORREA-DA-SILVA, FELIPE; CASTOLDI, ANGELA; BAKKER, NIKKI VAN TEIJLINGEN; DAVANZO, GUSTAVO GASTAO; CASTELUCCI, BIANCA; PEREIRA, JESSICA APARECIDA DA SILVA; CURTIS, JONATHAN; et al. Leptin Signaling Suppression in Macrophages Improves Immunometabolic Outcomes in Obesity. Diabetes, v. 71, n. 7, p. 16-pg., 2022-07-01. (13/07607-8, 19/06372-3, 18/19338-5, 16/23328-0, 19/25973-8, 20/16030-0, 19/19435-3)

MONTEIRO, LAUAR; DA SILVA PEREIRA, JESSICA APARECIDA; PALHINHA, LOHANNA; MORAES-VIEIRA, PEDRO MANOEL M.. Leptin in the regulation of the immunometabolism of adipose tissue-macrophages. Journal of Leukocyte Biology, v. 106, n. 3, p. 14-pg., 2019-09-01. (15/15626-8, 17/00079-7, 16/23328-0)

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)

CASTOLDI, ANGELA; MONTEIRO, LAUAR B.; BAKKER, NIKKI VAN TEIJLINGEN; SANIN, DAVID E.; RANA, NISHA; CORRADO, MAURO; CAMERON, ALANNA M.; HAESSLER, FABIAN; MATSUSHITA, MAI; CAPUTA, GEORGE; et al. Triacylglycerol synthesis enhances macrophage inflammatory function. NATURE COMMUNICATIONS, v. 11, n. 1, AUG 14 2020. (16/23328-0)

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)

MONTEIRO, Lauar de Brito. The study of the metabolic modulation of macrophages by leptin. 2021. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.