Social Stress Increases Vulnerability to High-Fat Diet-Induced Insulin Resistance by Enhancing Neutrophil Elastase Activity in Adipose Tissue.

Shinichiro Motoyama,Hiroshi Kubota,Noriyuki Wakana,Masakazu Ibi,Daisuke Miyawaki,Satoaki Matoba,Takeshi Sugimoto,Takehiro Ogata,Masakazu Kikai,Chihiro Yabe-Nishimura,Kensuke Terada,Makoto Saburi,Hiroyuki Yamada,Keita Yamamoto,Daisuke Kami,Naotoshi Wada

doi:10.3390/cells9040996

Abstract

Social stress (SS) has been linked to the development of cardiovascular disease (CVD), which is closely associated with insulin resistance (IR); however, the causal effect of SS on IR remains unclear. The 8-week-old male C57BL/6 mice were exposed to SS by housing with a larger CD-1 mouse in a shared home cage without physical contact for 10 consecutive days followed by high-fat diet (HFD) feeding. Control mice were housed in the same cage without a CD-1 mouse. After 6 weeks of HFD, insulin sensitivity was significantly impaired in stressed mice. While the percentage of classically activated macrophages in epididymal white adipose tissue (eWAT) was equivalent between the two groups, the percentage of lymphocyte antigen 6 complex locus G6D (Ly-6G)/neutrophil elastase (NE)-double positive cells markedly increased in stressed mice, accompanied by augmented NE activity assessed by ex vivo eWAT fluorescent imaging. Treatment with an NE inhibitor completely abrogated the insulin sensitivity impairment of stressed mice. In vitro NE release upon stimulation with a formyl peptide receptor 1 agonist was significantly higher in bone marrow neutrophils of stressed mice. Our findings show that SS-exposed mice are susceptible to the development of HFD-induced IR accompanied by augmented NE activity. Modulation of neutrophil function may represent a potential therapeutic target for SS-associated IR.

Highlights

Social stress (SS) has been associated with the development of cardiovascular disease (CVD) [1,2].SS is associated with the development of metabolic syndrome and type 2 diabetes mellitus (T2DM) [3,4], in which insulin resistance (IR) plays a critical role [5,6]
We did not examine the effects of longer periods of SS on insulin resistance in the lean mice, we examined the effect of repeated social defeat (RSD) that allowed for direct physical contact for 10 min each day during the 10 days of SS, leading to the development of depression-like behavior [18]
We showed for the first time that SS increases the vulnerability to high-fat diet (HFD)-induced IR

Summary

Introduction

SS is associated with the development of metabolic syndrome and type 2 diabetes mellitus (T2DM) [3,4], in which insulin resistance (IR) plays a critical role [5,6]. CVD than healthy individuals [8], SS-induced IR is thought to be a key contributor to the development of SS-related CVD; this precise mechanism has not been fully investigated. Previous studies have investigated the effect of SS on adipose tissue inflammation as a critical contributor to the development of IR [9,10]; cellular and molecular mechanisms of SS-induced. Recent studies showed that activation of neutrophil elastase (NE) was involved in the development of IR through impairment of insulin signaling [16,17]

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Results

Conclusion