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

Abstract

OBJECTIVES: (1) To investigate whether modulation of the cannabinoid type 1 receptor (CB1R) directly regulates the production of adiponectin (ApN) and other adipokines in omental adipose tissue (OAT) of obese subjects, (2) to establish in which cellular fraction of OAT the effects of CB1R blockade take place and (3) to unravel the underlying mechanisms. SUBJECTS AND METHODS: OAT was obtained from 30 obese subjects (body mass index: 40.6±1.3 kg m À 2 ) undergoing abdominal surgery. Primary cultures of explants or of freshly isolated adipocytes or stromal-vascular cells (SVCs) were used. RESULTS: In OAT explants, the CB1R blocker Rimonabant upregulated ApN gene expression. mRNA abundance of omentin that exhibits insulin-sensitizing properties was upregulated as well. Conversely, mRNA levels of two pro-inflammatory cytokines, macrophage inflammatory protein (MIP)-1b and interleukin (IL)-7 were downregulated. We next examined where these effects took place within OAT. CB1R expression was similar in both cellular fractions. In isolated mature adipocytes, blockade of CB1R reproduced the increase of ApN mRNA and the decrease of IL-7 mRNA, while inducing a rise of ApN secretion into the medium. In isolated SVC, gene expression of omentin, which is restricted to this fraction, was augmented, while that of MIP-1b was diminished. Finally, we deciphered the mechanisms leading to ApN regulation by the endocannabinoid system (ES). We first established that ApN regulation was actually mediated by the CB1R: ApN gene expression was upregulated by Rimonabant and downregulated by the CB1R agonist arachidonyl-2-chloroethylamide (ACEA). Upregulation of ApN by Rimonabant was unaltered by inhibiting cAMP production. However, downregulation of ApN by ACEA was fully reversed by an inhibitor of p38 mitogen-activated protein kinase (p38MAPK) and ACEA increased p38MAPK phosphorylation. CONCLUSIONS: Blockade of CB1R attenuates the inflammatory state in both cellular fractions of OAT either by increasing ApN and omentin production or by decreasing mRNAs of MIP-1b and IL-7. ApN regulation by the ES partly involves p38MAPK.

Changes in IGF-I, urinary free cortisol and adipokines during dronabinol therapy in anorexia nervosa: Results from a randomised, controlled trial

“…These results are consistent with in vitro results of Perwitz et al [28] and with the increase in adiponectin levels induced by the CBR1 antagonist rimonaband in humans, both in vitro [30] and in vivo [29]. Even though the effect of dronabinol might appear negligible, our finding raises the question whether the increased cannabinoid signalling -with higher doses and long-term treatment -may negatively affect insulin sensitivity in this group of patients.…”

“…Furthermore, adiponectin decreased during CBR1 receptor stimulation in vitro [28], while it increased during CBR1 antagonist stimulation in vitro as well as in vivo [29,30]. According to our current information, the effects of CBR1 stimulation on the endogenous adipokine secretion have not previously been documented in patients with AN.…”

Deletion of G-protein-coupled receptor 55 promotes obesity by reducing physical activity

“…Thus, even though fat mass is increased in GPR55 -/-mice, due to the potential opposing effect of GPR55 deletion on inflammation, the inflammation profile of adipose tissues of GPR55 -/-mice remain unchanged. Ge et al showed that pharmacological blockers of endocannabinoids up-regulate adiponectin expression in visceral fat of obese subjects to elicit anti-inflammatory effects 43 .…”

Adipose Tissue as an Endocrine Organ: An Update on Pro-inflammatory and Anti-inflammatory Microenvironment

“…In obese patients, the CB1 receptor blocker rimonabant upregulated adiponectin mRNA expression in omental AT explants (Ge et al, 2013). Likewise, obese and diabetic patients treated with 20 mg rimonabant daily exhibited an increase in adiponectin levels (Després et al, 2005(Després et al, , 2009Rosenstock et al, 2008).…”