Soluble (pro)renin receptor treats metabolic syndrome in mice with diet-induced obesity via interaction with PPARγ.

Fei Wang,Kexin Peng,Chang-Jiang Zou,Tianxin Yang,Long Zhao,Shiying Xie,Kevin T Yang,Chuanming Xu,Renfei Luo

doi:10.1172/jci.insight.128061

Abstract

The therapies available for management of obesity and associated conditions are limited, because they are often directed toward an individual component of metabolic syndrome and are associated with adverse effects. Here, we report the multifaceted therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed sPRR-His, in a mouse model of diet-induced obesity (DIO). In the DIO model, 2-week administration of sPRR-His lowered body weight and remarkably improved multiple metabolic parameters in the absence of fluid retention. Conversely, inhibition of endogenous sPRR production by PF429242 induced diabetes and insulin resistance, both of which were reversed by the sPRR-His supplement. At the cellular level, sPRR-His enhanced insulin-induced increases in glucose uptake via upregulation of phosphorylated AKT and protein abundance of glucose transporter 4. Promoter and gene expression analysis revealed PRR as a direct target gene of PPARγ. Adipocyte-specific PPARγ deletion induced severe diabetes and insulin resistance associated with reduced adipose PRR expression and circulating sPRR. The sPRR-His supplement in the null mice nearly normalized blood glucose and insulin levels. Additionally, sPRR-His treatment suppressed DIO-induced renal sodium-glucose cotransporter-2 (SGLT2) expression. Overall, sPRR-His exhibits a therapeutic potential in management of metabolic syndrome via interaction with PPARγ.

Highlights

The prevalence of overweight and obese persons has dramatically increased during the past 2 decades, with 65% of adults in the United States being overweight and 31% being obese [1, 2]
We further explored the in vivo role of soluble (pro)renin receptor (sPRR) in mediating the metabolic action of PPARγ in white adipose tissue (WAT)
Despite no obvious differences in body weight in the mice, sPRR-His treatment significantly lowered blood glucose (Figure 10F) and plasma insulin (Figure 10G) and improved glucose tolerance test (GTT) (Figure 10H) and insulin tolerance test (ITT) results (Figure 10I) in FKO mice. These findings suggest that suppressed sPRR production in WAT may be directly responsible for diabetes and insulin resistance induced by adipose-specific PPARγ deletion

Summary

Introduction

The prevalence of overweight and obese persons has dramatically increased during the past 2 decades, with 65% of adults in the United States being overweight and 31% being obese [1, 2]. The International Diabetes Federation estimates that one-quarter of the world’s adults are affected by metabolic syndrome and indicates that the expense for prevention and treatment of this disease is astronomical [3]. Antidiabetic therapies, such as metformin, insulin, dipeptidyl peptidase-4, and glucagon-like peptide-1, are used only for glycemic control and have little benefit for other components of metabolic syndrome [4]. These therapies are often associated with adverse effects, for example, one class of highly effective antidiabetic drugs, thiazolidinediones (TZDs), causes weight gain and fluid retention [5,6,7,8]. A multifaceted approach is desperately needed to simultaneously target multiple components of metabolic syndrome and to improve the safety profile

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Conclusion