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

Arjun Singh Kaushik; Vipul Agarwal; Neeraj Kumar; Mujeeba Rehman; Rishabh Chaudhary; Siddhi Srivastava; Sukriti Srivastava; Vikas Mishra

doi:10.1016/j.bbrc.2025.151567

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

Biochem Biophys Res Commun. 2025 Apr 5:756:151567. doi: 10.1016/j.bbrc.2025.151567. Epub 2025 Mar 4.

Authors

Arjun Singh Kaushik¹, Vipul Agarwal², Neeraj Kumar¹, Mujeeba Rehman¹, Rishabh Chaudhary¹, Siddhi Srivastava¹, Sukriti Srivastava¹, Vikas Mishra³

Affiliations

¹ Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226 025, (U.P.), India.
² MIT College of Pharmacy, Ram Ganga Vihar Phase-II, Moradabad, 244001, (U.P.), India.
³ Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, (A Central University), Vidya Vihar, Raebareli Road, Lucknow, 226 025, (U.P.), India. Electronic address: dr.vikasmishra@bbau.ac.in.

PMID: 40056501
DOI: 10.1016/j.bbrc.2025.151567

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.

Keywords: Chronic unpredictable stress; Metabolic syndrome; Sirtuin-6; Vagus nerve stimulation.

Publication types

Validation Study
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Animals
Blood Glucose
Hypertension / etiology
Hypertension / therapy
Insulin Resistance
Lipids / blood
Liver / enzymology
Liver / pathology
Male
Metabolic Syndrome* / etiology
Metabolic Syndrome* / metabolism
Metabolic Syndrome* / therapy
Pancreas / enzymology
Pancreas / pathology
Rats, Wistar
Sirtuins* / metabolism
Stress, Psychological* / blood
Stress, Psychological* / complications
Stress, Psychological* / pathology
Vagus Nerve Stimulation*

Substances

Sirtuins
Blood Glucose
Lipids
AMP-Activated Protein Kinases