Oxytocin Protects against Stress-Induced Cell Death in Murine Pancreatic β-Cells.

Sayaka Watanabe,Taku Kaitsuka,Fan-Yan Wei,Kazuhito Tomizawa,Nanami Matsunaga,Tomomi Matsunaga

doi:10.1038/srep25185

Abstract

Oxytocin (Oxt) is a key neuropeptide that regulates maternal behaviors as well as social behaviors in mammals. Interestingly, recent studies have shown that the impairment of Oxt signaling is associated with the disturbance of metabolic homeostasis, resulting in obesity and diabetes. However, the molecular mechanism by which Oxt signaling controls metabolic responses is largely unknown. Here, we report that Oxt signaling attenuates the death of pancreatic beta cells in islets exposed to cytotoxic stresses. The protective effect of Oxt was diminished in islets isolated from oxytocin receptor knockout (Oxtr−/−) mice. Oxtr−/− mice developed normally, but exhibited impaired insulin secretion and showed glucose intolerance under a high-fat diet. Mechanistically, the deficiency of Oxtr impaired MAPK/ERK-CREB signaling, which exaggerated the endoplasmic reticulum stress response and ultimately increased the death of beta cells in pancreatic islets under stressed conditions. These results reveal that Oxt protects pancreatic beta cells against death caused by metabolic stress, and Oxt signaling may be a potential therapeutic target.

Highlights

Oxytocin (Oxt) is a multifunctional hormone consisting of a mature polypeptide of nine amino acids[1]
By Student’s t-test adjusted for multiple comparison. (E) Cell death was measured in islets isolated from wildtype (WT) and oxytocin receptor (Oxtr)−/− mice treated with 100 pM oxytocin and a cytokine mixture for 24 hours. *P < 0.05 by Student’s t-test. n = 8. (F) Cell death was measured in islets isolated from wild-type mice treated with 1 nM vasopressin and a cytokine mixture for 24 hours. n = 12
Given the impaired metabolic homeostasis in mice and humans with deficiency of Oxt signaling[13,14,15], we hypothesized that Oxt signaling is involved in anti-cell death signaling in pancreatic islets

Summary

Introduction

Oxytocin (Oxt) is a multifunctional hormone consisting of a mature polypeptide of nine amino acids[1]. The involvement of Oxt signaling in metabolism has been confirmed in a mouse model with the genetic deletion of either Oxy or Oxtr. Recent epidemic studies showed that breast-feeding is likely to be associated with a lower incidence of type 2 diabetes[18,19] Taken together, these results suggest that Oxt signaling has a beneficial effect in metabolic homeostasis.

Methods

Results

Conclusion