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 a 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)