Stimulation of auricular vagus nerve ameliorates chronic stress induced metabolic syndrome via activation of Sirtuin-6

Abstract

Chronic stress is one of the potential causes of the progression of metabolic syndrome (MS). Chronic stress decreases the release of Sirtuin-6 (SIRT6), which regulates MS by controlling glucose, insulin, lipids, and hypertension. Vagus nerve stimulation (VNS) activates SIRT6 via the cholinergic anti-inflammatory pathway (CAP). However, the effectiveness of VNS therapy for treating MS induced by chronic stress has not yet been studied. In this study, we first validated a rat model of chronic unpredictable stress (CUS) and assessed the characteristic features of MS. The CUS rats were exposed to random stressors daily for 8 weeks. The stress response was then confirmed by behavioral alteration and elevated serum corticosterone levels in rats, as measured by various behavioral tests and an ELISA kit, respectively. The MS characteristics in CUS rats were assessed using measurements of fasting blood glucose (FBG), systolic blood pressure (SBP), lipid indices, insulin levels, and HOMA-IR. The stressed animals demonstrated a rise in FBG, SBP, and insulin along with altered lipid indices. After CUS, the rats were treated with VNS (6 Hz, 1.0 ms, 6 V, for 40 min × 14 days, alternatively), and their metabolic activity and vagal flow were assessed. Moreover, SIRT6 and AMP-activated protein kinase (AMPK) expression in rats was also assessed by immunohistochemistry and mRNA expression of liver and pancreatic tissue. SIRT6 and AMPK expression was decreased in CUS animals. Interestingly, VNS treatment attenuated CUS induced MS-associated parameters. These results indicate that VNS may be a beneficial complementary and non-pharmacological method for managing CUS-associated MS.