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Participation of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in the development of insulin resistance prevention

Abstract

Insulin resistance is defined as a state of reduced tissue responsiveness to normal circulating levels of insulin. It is resulted of a multifactorial process influenced by genetic and environmental factors. Among these factors, low-grade chronic inflammation induced by obesity is recognized as one of its main determinants. Similar to insulin-dependent metabolically active tissues, neurons also develop insulin resistance, resulting in neuronal damage and subsequent neurological dysfunction, such as impaired cognitive function and the development of dementia, including Alzheimer's disease. A possible shared mechanism between the metabolic and cognitive disorders derived from insulin resistance in the brain is the inflammatory process. The inflammatory response to the presence of a pathogen (innate immune response) is controlled by a mechanism involving the central nervous system (CNS), the vagus nerve, macrophages, acetylcholine and the inhibition of the expression of inflammatory cytokines, called cholinergic anti-inflammatory reflex (CAR). ±7nAChR receptors, when stimulated by acetylcholine, reduce TNF± expression activating STAT3 protein, diminishing the inflammatory response. However, the expression of ±7nAChR is significantly reduced in adipose tissue of obese individuals and in offspring of obese mothers, suggesting the modulation by factors associated with the development of obesity. Pro-inflammatory cytokines play an important role in the development of insulin resistance in both peripheral and CNS tissues. Thus, it seems reasonable to believe that damage to CAR when associated with an inflammatory environment may contribute to damage in hormonal signaling. In addition, the studies conducted to date, while suggesting this relationship, did not investigate the molecular mechanism involved. In this sense, we are interested in investigating the mechanisms that may affect the function of cholinergic anti-inflammatory pathway and its relationship with the development of insulin resistance. As model for the study we intend to use neuronal (GT1-7) and microglia (BV-2) cell lines. Additionally, one in vivo model, mice exposed to a high fat diet (HFD), will be used to evaluate the effect of HFD in the hypothalamic. In both lines we will use a plasmid vector to induce or inhibit ±7nAChR expression. In vivo studies will be performed on a model of obesity induced by HFD (3 days of diet), which showed in the previous studies a significant reduction of ±7nAChR expression. In the in vitro model, the efficiency of insulin signaling (activation of AKT) in a pro-inflammatory environment will be performed after overexpression or inhibition of ±7nAChR expression. In vivo it is intended to evaluate in which hypothalamic cell type the consumption of HFD for 3 days affects the expression of ±7nAChR and how this can modulate the expression of cytokines in this region of the CNS. From the epigenetic point of view, we intend to evaluate the methylation of the CHRNA7 gene (responsible for ±7nAChR expression) and if the inflammatory environment may potentiate the methylation of this gene. (AU)

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Scientific publications (4)
(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)
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. Web of Science Citations: 0.
VERAS, ALANA CAROLINA COSTA; DOS SANTOS, TAMIRES; MARTINS, ISIS DE CASSIA ALVES; DE SOUZA, CAMILLA MENDES; AMARAL, CAMILA LIBARDI; FRANCO, BEATRIZ DA SILVA; HOLANDA, ALESSANDRO SPENCER DE SOUZA; ESTEVES, ANDREA MACULANO; MILANSKI, MARCIANE; TORSONI, ADRIANA SOUZA; IGNACIO-SOUZA, LETICIA MARTINS; TORSONI, MARCIO ALBERTO. Low-Dose Coconut Oil Supplementation Induces Hypothalamic Inflammation, Behavioral Dysfunction, and Metabolic Damage in Healthy Mice. MOLECULAR NUTRITION & FOOD RESEARCH, v. 65, n. 10 APR 2021. Web of Science Citations: 0.
COSTA, S. O.; SOUZA, C. M.; LANZA, P. G.; SARTORI, J. O.; IGNACIO-SOUZA, L. M.; CANDREVA, T.; RODRIGUES, H. G.; TORSONI, A. S.; MILANSKI, M.; TORSONI, M. A. Maternal high fat diet consumption reduces liver alpha7 nicotinic cholinergic receptor expression and impairs insulin signalling in the offspring. SCIENTIFIC REPORTS, v. 10, n. 1 JAN 8 2020. Web of Science Citations: 3.
PARRAS SOUZA, ANELISE CRISTINA; SOUZA, CAMILLA MENDES; AMARA, CAMILA LIBARDI; LEMES, SIMONE FERREIRA; SANTUCCI, LETICIA FOGLIA; MILANSKI, MARCIANE; TORSONI, ADRIANA SOUZA; TORSONI, MARCIO ALBERTO. Short-Term High-Fat Diet Consumption Reduces Hypothalamic Expression of the Nicotinic Acetylcholine Receptor alpha 7 Subunit (alpha 7nAChR) and Affects the Anti-inflammatory Response in a Mouse Model of Sepsis. FRONTIERS IN IMMUNOLOGY, v. 10, MAR 22 2019. Web of Science Citations: 0.

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