GPNMB plays a protective role against obesity-related metabolic disorders by reducing macrophage inflammatory capacity

Adam Prabata,Koji Ikeda,Elda Putri Rahardini,Ken-Ichi Hirata,Noriaki Emoto

doi:10.1016/j.jbc.2021.101232

Abstract

Obesity is a global health problem that is often related to cardiovascular and metabolic diseases. Chronic low-grade inflammation in white adipose tissue (WAT) is a hallmark of obesity. Previously, during a search for differentially expressed genes in WAT of obese mice, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB), of which expression was robustly induced in pathologically expanded WAT. Here, we investigated the role of GPNMB in obesity-related metabolic disorders utilizing GPNMB-deficient mice. When fed a high-fat diet (HFD), GPNMB-deficient mice showed body weight and adiposity similar to those of wild-type (WT) mice. Nonetheless, insulin and glucose tolerance tests revealed significant obesity-related metabolic disorders in GPNMB-KO mice compared with WT mice fed with HFD. Chronic WAT inflammation was remarkably worsened in HFD-fed GPNMB-KO mice, accompanied by a striking increase in crown-like structures, typical hallmarks for diseased WAT. Macrophages isolated from GPNMB-KO mice were observed to produce more inflammatory cytokines than those of WT mice, a difference abolished by supplementation with recombinant soluble GPNMB extracellular domain. We demonstrated that GPNMB reduced the inflammatory capacity of macrophages by inhibiting NF-κB signaling largely through binding to CD44. Finally, we showed that macrophage depletion by addition of clodronate liposomes abolished the worsened WAT inflammation and abrogated the exacerbation of metabolic disorders in GPNMB-deficient mice fed on HFD. Our data reveal that GPNMB negatively regulates macrophage inflammatory capacities and ameliorates the WAT inflammation in obesity; therefore we conclude that GPNMB is a promising therapeutic target for the treatment of metabolic disorders associated with obesity.

Highlights

Obesity is increasing worldwide; its prevalence has nearly tripled between 1975 and 2016, and over 650 million adults were obese in 2016 according to a report of World Health Organization
glycoprotein nonmetastatic melanoma protein B (GPNMB) showed relatively high expression in the white adipose tissue (WAT) comparing to other tissues (Fig. 1C), and its expression was predominant in the stromal vascular fraction (SVF) rather than in mature adipocytes in the WAT of lean mice (Fig. 1D)
GPNMB expression was substantially enhanced in mature adipocytes to the levels beyond that in the SVF, while its expression was increased in the SVF (Fig. 1F)

Summary

Introduction

Obesity is increasing worldwide; its prevalence has nearly tripled between 1975 and 2016, and over 650 million adults were obese in 2016 according to a report of World Health Organization. We explored a role of GPNMB in obesity using GPNMB-deficient mice and revealed its protective role in obesity-related metabolic disorders by reducing macrophage inflammatory capacities. Because the WAT inflammation is closely associated with the adipocyte and immune cell interaction, we have performed signal sequence trap, a cloning strategy for secreted and type-I membrane proteins, using cDNA libraries prepared from the WAT of obese mice.

Results

Conclusion