Obesity is a major risk factor for type 2 diabetes mellitus and insulin resistance (IR). In the state of obesity, excess fat accumulates in the liver, a key organ in systemic metabolism, altering the inflammatory and metabolic signals contributing substantially to the development of hepatic IR. Current therapies for these metabolic disorders have not been able to reverse their rapidly rising prevalence. One of the reasons is that the effects of existing drugs are predominantly non-lasting [1,2]. The vagus nerve (VN) is known to play an essential role in maintaining metabolic homeostasis while decreased VN activity has been suggested to contribute to obesity associated metabolic syndrome [3,4]. Several studies have reported that activation of α7 nicotinic acetylcholine receptor (α7nAChR) cholinergic signaling with or without VN intervention has protective effects against obesity-related inflammation and other metabolic complications [5]. However, the molecular mechanisms are still not elucidated. Exaggerated endoplasmic reticulum (ER) stress and consequent dysregulated inflammation has been implicated in the development of lipid accumulation and IR [6]. Whether targeting α7nAChR can regulate IR through these pathways is rarely reported. Accordingly, the present proposal posits that activation of the α7nAChR by VNS attenuates ER stress induced inflammation, thus ameliorating hepatic IR in Kupffer cell. We will focus on the specific interaction between vagal cholinergic activity and the modulation of ER stress induced inflammation via the α7nAChR associated pathway during IR development. Recently, the Endocrine Society has emphasized the absence of specific evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding underlying mechanisms of obesity [7]. In this proposal, we assign a significant role to α7nAChR in obesity-induced hepatic IR, and suggest a possible therapeutic strategy with VNS intervention.
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