• Biomolecules & Therapeutics
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• 제23권3호
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• pp.218-224
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• 2015

Endocannabinoids can affect multiple cellular targets, such as cannabinoid (CB) receptors, transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and peroxisome proliferator-activated receptor ${\gamma}$($PPAR{\gamma}$). The stimuli to induce adipocyte differentiation in hBM-MSCs increase the gene transcription of the $CB_1$ receptor, TRPV1 and $PPAR{\gamma}$. In this study, the effects of three endocannabinoids, N-arachidonoyl ethanolamine (AEA), N-arachidonoyl dopamine (NADA) and 2-arachidonoyl glycerol (2-AG), on adipogenesis in hBM-MSCs were evaluated. The adipocyte differentiation was promoted by AEA whereas inhibited by NADA. No change was observed by the treatment of non-cytotoxic concentrations of 2-AG. The difference between AEA and NADA in the regulation of adipogenesis is associated with their effects on $PPAR{\gamma}$ transactivation. AEA can directly activate $PPAR{\gamma}$. The effect of AEA on $PPAR{\gamma}$ in hBM-MSCs may prevail over that on the $CB_1$ receptor mediated signal transduction, giving rise to the AEA-induced promotion of adipogenesis. In contrast, NADA had no effect on the $PPAR{\gamma}$ activity in the $PPAR{\gamma}$ transactivation assay. The inhibitory effect of NADA on adipogenesis in hBM-MSCs was reversed not by capsazepine, a TRPV1 antagonist, but by rimonabant, a $CB_1$ antagonist/inverse agonist. Rimonabant by itself promoted adipogenesis in hBM-MSCs, which may be interpreted as the result of the inverse agonism of the $CB_1$ receptor. This result suggests that the constantly active $CB_1$ receptor may contribute to suppress the adipocyte differentiation of hBM-MSCs. Therefore, the selective $CB_1$ agonists that are unable to affect cellular $PPAR{\gamma}$ activity inhibit adipogenesis in hBM-MSCs.

• Biomolecules & Therapeutics
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• 제17권4호
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• pp.348-352
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• 2009

Over the last decade, the incidence of overweight and obesity has nearly doubled in many countries and is considered a pandemic. Obesity was identified as a major risk factor for cardiovascular disease as the same level as smoking and diabetes. Visceral fat is considered one of the key contributors to outcome and certain ethnic groups such as Asians seem to be more affected than others. Weight reduction through lifestyle changes was found to be impactful to improve overall health, but weight loss and maintenance thereof is limited and difficult to sustain. Surgical intervention demonstrated a greater weight loss in the severely obese and was associated with improved all-cause mortality. Despite numerous pharmacological targets and a high medical need, only few drugs have been successfully developed. Earlier studies with amphetamine-derived compounds showed significant weight loss but their critical safety profiles led to market withdrawals and disappointment. More recent compounds; orlistat - a lipase inhibitor, rimonabant - a cannaboid-1-receptor antagonist, and sibutramine - a combined serotonin/norepinephrine re-uptake inhibitor, all demonstrated similar significant efficacy; however, they carry specific safety profiles making them unsuitable for every patient. The main limitation of pharmacotherapy is the absence of clear benefit-risk assessments through outcome studies. Such a study - the SCOUT trial - was designed to compare sibutramine versus placebo and the effect on morbidity and mortality in nearly 10,000 obese patients with additional risk factors. Such studies could provide new scientific evidence for obesity treatment and may support future pharmacological approaches.