The study of the metabolic and functional modulation of macrophages by leptin

• Grant number: 18/19338-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: January 22, 2019
• End date: November 29, 2019
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Lauar de Brito Monteiro
• Supervisor: Edward J. Pearce
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Max Planck Society, Freiburg, Germany
• Associated to the scholarship: 16/23328-0 - Study of the metabolic regulation of macrophages by leptin, BP.DD

Abstract

It is still not entirely elucidated how pathological conditions with excess of nutrients (glucose and lipids) and growth factors (leptin, insulin) in obesity and insulin resistance can modulate metabolic function of immune cells. Leptin is an adipokine produced by the adipose tissue and regulates food intake. Leptin concentration indicates the amount of energy available to be used by the organism. The association between obesity and other inflammatory/autoimmune conditions has been suggested in several observational studies. In obesity, leptin concentration is found elevated, and these values decrease during malnutrition. Leptin activates the STAT3 pathway and also the PI3K/AKT signalling. The PI3K/AKT pathway results in the activation of mTOR, an intracellular kinase that senses the nutritional and metabolic state of the cell. Animals deficient in leptin or leptin receptor have several metabolic and immunologic alterations. Leptin signalling results in the differentiation of TCD4 cells towards a proinflammatory profile, with enhanced circulating Th17 cells. In the same way, this signalling suppresses the anti-inflammatory profile by blocking regulatory T cess (Treg) differentiation. In obese mice and humans, a switch into a pro-inflammatory (M1) profile in adipose tissue resident macrophages (ATMs) is observed and in lean mice and humans there is a predominance of anti-inflammatory (M2) macrophages. It is possible that leptin might indirectly regulate macrophage polarization, since in vitro leptin supplementation during macrophage activation induces the production of increased amounts of pro-inflammatory cytokines. In this project, we will use an obesity model for the induction of low grade systemic inflammation in animals with a specific deletion of the leptin receptor in myeloid cells. The mechanism by which leptin, through mTOR activation, regulates ATMs metabolism is still unknown. Using mass spectrometry-based approaches, we aim to identify metabolic pathways associated with macrophage activation and function. The comprehension of immunometabolic mechanisms involved in the pathogenesis of these diseases may lead to the discovery of new metabolic-dependent inflammation-induced pathways, as well as novel therapeutic approaches. (AU)

Scientific publications

(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 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)