GPNMB protects against obesity-related metabolic disorders by attenuating macrophage-derived inflammation in white adipose tissue through CD44 receptor-dependent mechanism

Abstract Introduction Obesity is a worldwide health issue frequently linked to cardiovascular disease. Obesity is closely associated with chronic low-grade inflammation in adipose tissue caused by macrophage infiltration and activation, which leads to metabolic disorders. We discovered glycoprotein non-metastatic melanoma protein B (GPNMB) as a gene that is robustly expressed in white adipose tissue of obese mice. Purpose We aim to elucidate the role of GPNMB in obesity and its related metabolic disorders. Methods We generated GPNMB-knockout (KO) mice and assessed body weight, insulin sensitivity, and inflammation-related phenotypes after 12 weeks of high fat-diet (HFD) feeding. For in vitro experiment, we isolated peritoneal macrophages from wild-type (WT) and GPNMB-KO mice to explore their inflammatory phenotypes. Results After HFD feeding, obesity-related metabolic disorders were markedly worsened in GPNMB-KO mice, assessed by insulin and glucose tolerance test, although the weight gain and adiposity were similar between WT and GPNMB-KO mice. Expression of inflammatory cytokines was significantly increased in WAT of GPNMB-KO mice, in addition to a remarkable increase in crown-like structures. Peritoneal macrophages isolated from GPNMB-KO mice exhibited higher inflammatory cytokine levels, and significantly impaired the adipocytes insulin sensitivity in an endocrine manner. Recombinant soluble GPNMB attenuated the inflammatory capabilities in peritoneal macrophages isolated from GPNMB-KO mice. We identified that GPNMB inhibits the NF-κB signaling through binding to the CD44 receptor, and therefore negatively regulates inflammatory responses in macrophages. Conclusion Our study demonstrates GPNMB as an adipokine that protects against obesity-related metabolic disorders by reducing macrophage-derived inflammation, which in turn improves adipocytes functions and consequently preserves systemic metabolic health. Therefore, GPNMB is an attractive therapeutic target for the treatment of obesity-related metabolic disorders. Funding Acknowledgement Type of funding sources: None.