Effect of the Cannabinoid Receptor-1 antagonist SR141716A on human adipocyte inflammatory profile and differentiation

Abstract

BackgroundObesity is characterized by inflammation, caused by increase in proinflammatory cytokines, a key factor for the development of insulin resistance. SR141716A, a cannabinoid receptor 1 (CB1) antagonist, shows significant improvement in clinical status of obese/diabetic patients. Therefore, we studied the effect of SR141716A on human adipocyte inflammatory profile and differentiation.MethodsAdipocytes were obtained from liposuction. Stromal vascular cells were extracted and differentiated into adipocytes. Media and cells were collected for secretory (ELISA) and expression analysis (qPCR). Triglyceride accumulation was observed using oil red-O staining. Cholesterol was assayed by a fluorometric method. 2-AG and anandamide were quantified using isotope dilution LC-MS. TLR-binding experiments have been conducted in HEK-Blue cells.ResultsIn LPS-treated mature adipocytes, SR141716A was able to decrease the expression and secretion of TNF-a. This molecule has the same effect in LPS-induced IL-6 secretion, while IL-6 expression is not changed. Concerning MCP-1, the basal level is down-regulated by SR141716A, but not the LPS-induced level. This effect is not caused by a binding of the molecule to TLR4 (LPS receptor). Moreover, SR141716A restored adiponectin secretion to normal levels after LPS treatment. Lastly, no effect of SR141716A was detected on human pre-adipocyte differentiation, although the compound enhanced adiponectin gene expression, but not secretion, in differentiated pre-adipocytes.ConclusionWe show for the first time that some clinical effects of SR141716A are probably directly related to its anti-inflammatory effect on mature adipocytes. This fact reinforces that adipose tissue is an important target in the development of tools to treat the metabolic syndrome.

Endocannabinoids regulate adipokine production and the immune balance of omental adipose tissue in human obesity

“…29 On the other hand, a synthetic cannabinoid upregulated proinflammatory adipokines in human fat cells, 15 while the selective CB1R blocker Rimonabant restored to basal levels the secretion of ApN, which was downregulated by lipopolysaccharide co-treatment. 16 Herein, we unambiguously show that a selective CB1R agonist (ACEA) decreased ApN expression, while a selective CB1R blocker upregulated ApN and concurrently downregulated the expression of several pro-inflammatory adipokines in both cellular fractions of OAT. The fact that we were able to disclose an effect of CB1R blockade even in basal conditions may be explained by the already enhanced cannabinoid tone in omental fat of obese subjects.…”

“…Few reports yielded controversial data on adipokine release by human fat cells. [14][15][16] These experiments were carried out on adipocytes differentiated in vitro from stromal precursors, which were isolated mainly from subcutaneous fat of non-obese subjects, 15,16 then submitted to pharmacological doses of adipogenic cocktails. However, omental rather than subcutaneous fat, as well as obesity are linked to the metabolic syndrome and abnormal endocannabinoid tone.…”

Role of the endocannabinoid system in diabetes and diabetic complications

“…Emerging data suggest that a dysregulated ECS has also direct deleterious effects on insulin sensitivity and glucose metabolism independently of weight gain. In adipose tissue, activation of the ECS enhances glucose uptake to increase energy storage in the form of de novo synthesized lipids, down-regulates adiponectin thereby affecting insulin sensitivity at distant organs and may favour local inflammation (Murumalla et al, 2011;Ge et al, 2013). In skeletal muscle, the CB1 receptor interferes with glucose uptake by inhibiting signalling pathways activated by insulin, including those required for plasma membrane translocation of glucose transporters.…”

The Fatty Acid Amide Hydrolase in Lymphocytes from Sedentary and Active Subjects

“…For instance, AEA inhibits synthesis and release of adiponectin, an insulin-sensitizing and antiinflammatory cytokine, while it increases synthesis and release of the pro-inflammatory adipocytokine visfatin, whose expression is regulated by insulin resistance-inducing hormones (24). Moreover, CB 1 antagonism decreases TNF-> secretion and restores adiponectin release from lipopolysaccharidetreated adipocytes (26).…”