Role of nicotinic acetylcholine receptors alpha7 (±7nAChR) in the hypothalamic control of energy homeostasis and association with central signaling of leptin in mice

• Grant number: 19/07615-7
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2019
• End date: July 31, 2022
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Marcio Alberto Torsoni
• Grantee: Marcio Alberto Torsoni
• Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
• City of the host institution: Limeira
• Associated researchers: Adriana Souza Torsoni

Abstract

Cholinergic signaling, mediated by the activation of muscarinic and nicotinic receptors, plays an important role in the regulation of the inflammatory response. However, the literature also shows that nicotinic receptors are able to promote the reduction of body weight and food intake. Acetylcholine receptors are widely expressed in different cell types and in the central nervous system their expression has been described in regions that control the control of energy homeostasis, metabolism and satiety. Activation of this receptor results in the activation of the JAK2 / STAT3 pathway and sharing proteins with leptin and insulin signaling pathways, which play an important role in the control of central energy homeostasis. The hypothalamus is the regulating center of energy homeostasis and the nicotinic acetylcholine receptor ±7nAChR is highly expressed in this region. Recently, we showed that consumption of hyperlipidic diet (HFD) for a short period of time is able to reduce the hypothalamic expression of the ±7nAChR receptor. Thus, we hypothesized that the hypothalamic receptor ±7nAChR participates in the control of homeostasis and inflammatory conditions early damage its expression in the hypothalamus, contributing to the development of metabolic damages. In this project we intend to investigate the role of the hypothalamic ±7nAChR subunit receptor in the control of energy homeostasis, its association with leptin signaling and how HFD is able to reduce the expression of this receptor. For this purpose we will use animal models with ±7nAChR receptor deletion (CHRNA7LoxP) in the cells of interest: microglia (LIZ-Cre), POMC (Cre-POMC) and AGRP-Cre neurons. To obtain these animal models we will use the Cre-LoxP system. We will perform in vitro studies with neuronal cell lineage to investigate the molecular mechanisms that connect receptor activation to the modulation of gene expression. In cell culture we intend to employ CRISPR-Cas9 technologies and knockdown with shRNA to delete/reduce ±7nAChR receptor expression. In the studies with the animal models we will perform analyzes of body and behavioral parameters (energy expenditure and ingestion) that will be evaluated after the consumption of HFD and compared with wild type mice. In order to reinforce the possible behavioral and corporeal findings we intend to perform molecular analyzes of the expression of NPY, POMC, cytokines, response to leptin and activation of inflammatory pathways using RT-PCR, western blot, confocal immunofluorescence and cytometry protocols. Similarly, in cell culture of neuronal lineage (mHypoA29) we also intend to carry out the studies to corroborate the molecular data that have been obtained in mice. With the development of this project another physiological mechanism can be associated to control of energy homeostasis and response to leptin, as well as to establish relationships between the damages caused by the consumption of HFD to its effects on hypothalamic expression of the ±7nAChR receptor. (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)

VERAS, ALANA CAROLINA COSTA; BRUZASCO, LARISSA DA SILVA; LOPES, ANA BEATRIZ PROFIRO; FRANCO, BEATRIZ DA SILVA; HOLANDA, ALESSANDRO SPENCER DE SOUZA; ESTEVES, ANDREA MACULANO; MILANSKI, MARCIANE; TORSONI, ADRIANA SOUZA; IGNACIO-SOUZA, LETICIA MARTINS; TORSONI, MARCIO ALBERTO. Supplementation with CO induces lipogenesis in adipose tissue, leptin and insulin resistance in healthy Swiss mice. Journal of Functional Foods, v. 106, p. 12-pg., 2023-06-04. (19/07615-7, 16/23484-1, 18/01863-6)

MARTINS, I. C. A.; CONTIERI, L. S.; AMARAL, C. L.; COSTA, S. O.; SOUZA, A. C. P.; IGNACIO-SOUZA, L. M.; MILANSKI, M.; TORSONI, A. S.; TORSONI, M. A.. Omega-3 Supplementation Prevents Short-Term High-Fat Diet Effects on the alpha 7 Nicotinic Cholinergic Receptor Expression and Inflammatory Response. Mediators of Inflammation, v. 2021, AUG 10 2021. (16/23484-1, 18/01863-6, 13/07607-8, 19/07615-7)

DO AMARAL, CAMILA LIBARDI; ALVES MARTINS, ISIS DE CASSIA; COSTA VERAS, ALANA CAROLINA; SIMABUCO, FERNANDO MOREIRA; ROSS, MICHAEL GLENN; DESAI, MINA; IGNACIO-SOUZA, LETICIA MARTINS; MILANSKI, MARCIANE; TORSONI, ADRIANA SOUZA; TORSONI, MARCIO ALBERTO. Activation of the alpha 7 Nicotinic Acetylcholine Receptor Prevents against Microglial-Induced Inflammation and Insulin Resistance in Hypothalamic Neuronal Cells. CELLS, v. 11, n. 14, p. 15-pg., 2022-07-01. (16/23833-6, 19/07615-7)