Reversal of inflammation by cannabinoid receptor type 1 (CB1) antagonist

Obesity associated subclinical inflammation is believed to be linked to an enhanced risk of metabolic disorders like insulin resistance, diabetes and cardiovascular disease. During the development of obesity an increased infiltration of macrophages into adipose tissue and an increased expression of inflammatory cytokines have been observed.

Macrophages can either adopt a pro-inflammatory M1 phenotype or an anti-inflammatory M2 phenotype. When stimulated by inflammation the M1 macrophages produce inflammatory cytokines like TNF-alpha and IL-6. The M2 macrophages, on the other hand, are involved in the suppression of inflammation by producing anti-inflammatory cytokines like IL-10. Both phenotypes are present in adipose tissue and a switch in phenotype from anti-inflammatory to pro-inflammatory has been observed during the onset of obesity in mice.

Several studies have reported an anti-inflammatory role of the cannabinoid receptor type 1 (CB1) antagonist SR141716. In addition to inducing weight loss, increasing blood HDL-cholesterol and decreasing circulating levels of triglycerides and insulin resistance, this anti-obesity drug has been shown to decrease plasma levels of the inflammatory marker CRP and increase the anti-inflammatory marker adiponectin. In rats, SR141716 has been shown to improve neurogenic inflammation and, in a rat model of arthritis, to improve arthritic conditions.

To investigate this further, researchers at Sanofi-Aventis studied the effect of SR141716 on macrophages as well as whether conditioned medium from SR141716 treated macrophages can influence insulin sensitivity in adipocytes from obese rats. The results showed that conditioned medium from macrophages isolated from obese rats inhibited insulin-stimulated glucose uptake in adipocytes by 73%, whereas when adipocytes were incubated with cultured medium from macrophages isolated from SR141716 treated obese rats the insulin-stimulated glucose uptake was fully restored. SR141716 was shown to reduce TNF-alpha secretion and increase IL-10 secretion from macrophages resulting in a rescue of insulin signaling in adipocytes.

In this study the Mercodia Ultrasensitive Rat Insulin ELISA was used to determine insulin concentrations.

Click on the following link to download the abstract: Miranville et al. (2010) Reversal of Inflammation-Induced Impairment of Glucose Uptake in Adipocytes by Direct Effect of CB1 Antagonism on Adipose Tissue Macrophages. Obesity (Silver Spring) Epub April 8