Endocannabinoid System Regulates Inflammation and Insulin resistance via Resistin

Abstract

Background Obesity is recognized as a significant risk factor for cardiovascular disease and dysregulation of the endocannabinoid system. Endocannabinoid system has been regarded as a modulator of food intake that affects the regulation of obesity and insulin resistance. Resistin is an adipokine and involved in metabolic disorders and inflammation. Here, we hypothesized that the endocannabinoid system regulates the CB1R positive monocytes expressing resistin, thus modulating inflammation and insulin resistance in humans. Methods and Results In human atheromatous arteries, CB1R was co-localized with resistin and the levels of resistin expressions were significantly higher in sorted CB1R positive cells. In CB1R positive cells, resistin expressions were increased by 2-AG and CB1 receptor blockade by SR141716 and AM251 reduced resistin expressions via the inhibition phosphorylation of p38 MAPKs. To test whether the endocannabinoid system regulates insulin resistance and inflammation in vivo, we used two animal models as humanized NOG mice and humanized resistin mice models. In both models, high fat diet increased insulin resistance, which was reversed by the treatment of CB1 receptor antagonists. Furthermore, the increase of CB1R, resistin and proinflammatory gene expressions induced by high fat diet was normalized in the normal diet in visceral fat tissues of both mice. Moreover, we confirmed that this process might be mediated by the infiltration of peripheral blood monocytes expressing resistin. Further studies including a migration assay and LC/MS/MS demonstrated that high fat diet increased the level of CB1 receptor ligand, promoting the migration and infiltration of CB1R positive monocytes. Conclusion Our study demonstrated that the endocannabinoid system modulates resistin expressions of human peripheral monocytes, thus regulating the infiltration of these cells into the tissues associated with insulin resistance and inflammation. These results provide an important insight into the pathophysiology of cardiometabolic disease and the development of new drugs.