Abstract
Hypertension and obesity are related to adipose tissue inflammation and insulin resistance, and both are important factors for the development of type II Diabetes mellitus. High serum osteoprotegerin (OPG) level has been reported in diabetic patients, and is considered a marker for future cardiovascular events. OPG is a decoy receptor of RANKL, and inhibits its binding to the receptor RANK. The RANKL system has been reported in bone, mammary gland development, immune cells communication, and we have previously reported its role in vascular calcification and potential cross-talk with Renin-angiotensin II system via ERK phosphorylation pathway. In this study, we examined the role of RANKL system in adipose tissue. High fat diet significantly increased the RANK-RANKL, ACE, AT1R as well as TNF alpha and MCP-1 mRNA expression in C57/BL6 and db/db mice adipose tissue. In vitro studies showed that RANKL expression increases following human pre adipocyte differentiation, and is further increased in the presence of Angiotensin II. We have found that PMA-activated monocytes (THP1) express higher level of RANK compared to non-stimulated monocytes, and that RANKL stimulation induces inflammatory cytokines expression in the presence of anti-OPG neutralizing antibody. Also, RANKL induced macrophage migration in boyden chamber assay dose dependently. OPG-/- mice under high fat diet presented increased number of crown-like structures in adipose tissue compared to wild type. Interestingly the deletion of AT1R in OPG-/-mice significantly decreased that macrophage infiltration, and inhibited the expression of inflammatory cytokines and RANKL system in adipose tissue. OPG-/- mice, known as the model of continuous activation of RANKL system, showed higher insulin level and insulin resistance compared to WT and AT1R-/-/OPG-/- mice. Overall, we propose that RANKL is activated in adipose tissue under high fat diet, and may contribute to insulin resistance by inducing macrophage recruitment and adipose tissue inflammation. Moreover, blockade of local renin-angiotensin II activation can also inhibit RANKL system activation in adipose tissue.
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