Role of RAGE in obesity-induced adipose tissue inflammation and insulin resistance

Ziqian Feng,Mao Luo,Jianbo Wu,Yi Li,Luochen Zhu,Xin Shu,Qian Gao,Michael A Hill,Liqun Wang,Zuoqin Du,Jiaqi Wu,Ni Chen

doi:10.1038/s41420-021-00711-w

Abstract

AbatractObesity is known to be associated with adipose tissue inflammation and insulin resistance. Importantly, in obesity, the accumulation of proinflammatory macrophages in adipose tissue correlates with insulin resistance. We hypothesized that the receptor for advanced glycation end products (RAGE) and associated ligands are involved in adipose tissue insulin resistance, and that the activation of the AGE–RAGE axis plays an important role in obesity-associated inflammation. C57BL/6J mice (WT) and RAGE deficient (RAGE−/−) mice were fed a high fat diet (HFD) and subjected to glucose and insulin tolerance tests. Epdidymal adipose tissue (eAT) was collected and adipose stromal vascular cells isolated using flow cytometry. Visceral adipose tissue macrophage polarization was assessed by quantitative real time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. In additional studies, cell trafficking was assessed by injecting labeled blood monocytes into recipient mice. RAGE−/− mice displayed improved insulin sensitivity and glucose tolerance, accompanied by decreased body weight and eAT mass. Exogenous methylglyoxal (MGO) impaired insulin-stimulated AKT signaling in adipose tissues from WT mice fed a normal chow diet, but not in RAGE−/− mice. In contrast, in obese mice, treatment with MGO did not reduce insulin-induced phosphorylation of AKT in WT-HFD mice. Moreover, insulin-induced AKT phosphorylation was found to be impaired in adipose tissue from RAGE−/−-HFD mice. RAGE−/− mice displayed improved inflammatory profiles and evidence for increased adipose tissue browning. This observation is consistent with the finding of reduced plasma levels of FFA, glycerol, IL-6, and leptin in RAGE−/− mice compared to WT mice. Collectively the data demonstrate that RAGE-mediated adipose tissue inflammation and insulin-signaling are potentially important mechanisms that contribute to the development of obesity-associated insulin resistance.

Highlights

Adipose tissue serves as an essential endocrine regulator in glucose homeostasis and is involved in the progression of obesity and type 2 diabetes mellitus (T2DM), at least in part, through the induction of a chronic inflammatory state
We found that receptor for advanced glycation end products (RAGE) deficiency potently reduces the recruitment of circulating monocytes to AT, suppresses M1 including IL-6, IL-1β, TNF-α, MCP-1, and CD11c, were significantly decreased in Epdidymal adipose tissue (eAT) from RAGE−/− -high fat diet (HFD) mice compared with WT
We examined whether RAGE significantly increased body weight compared to RAGE−/−-HFD plays a role in mediating insulin sensitivity in subcutaneous mice (Fig. 1F, G)

Summary

Introduction

Adipose tissue serves as an essential endocrine regulator in glucose homeostasis and is involved in the progression of obesity and type 2 diabetes mellitus (T2DM), at least in part, through the induction of a chronic inflammatory state. Adipose tissue insulin resistance has been associated with dysregulated insulin signaling, impaired glucose uptake, and lipid homeostasis [1, 2]. RAGE appears to be involved in the progression of obesity, correlating with adipose tissue inflammation, adipocyte hypertrophy, and insulin sensitivity [5, 6]. High-fat feeding elevates the levels of RAGE ligands, HMGB1 and carboxymethyl lysine (CML)-AGE, in the liver and adipose tissue [6]

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