Abstract
(1) Background: Acute administration of the cannabinoid receptor 1 (CB1R) inverse agonist Rimonabant (SR141716A) to fed Wistar rats was shown to elicit a rapid and short-lasting elevation of serum free fatty acids. (2) Methods: The effect of Rimonabant on lipolysis in isolated primary rat adipocytes was studied to raise the possibility for direct mechanisms not involving the (hypothalamic) CB1R. (3) Results: Incubation of these cells with Rimonabant-stimulated lipolysis to up to 25% of the maximal isoproterenol effect, which was based on both CB1R-dependent and independent mechanisms. The CB1R-dependent one was already effective at Rimonabant concentrations of less than 1 µM and after short-term incubation, partially additive to β-adrenergic agonists and blocked by insulin and, in part, by adenosine deaminase, but not by propranolol. It was accompanied by protein kinase A (PKA)-mediated association of hormone-sensitive lipase (HSL) with lipid droplets (LD) and dissociation of perilipin-1 from LD. The CB1R-independent stimulation of lipolysis was observed only at Rimonabant concentrations above 1 µM and after long-term incubation and was not affected by insulin. It was recapitulated by a cell-free system reconstituted with rat adipocyte LD and HSL. Rimonabant-induced cell-free lipolysis was not affected by PKA-mediated phosphorylation of LD and HSL, but abrogated by phospholipase digestion or emulsification of the LD. Furthermore, LD isolated from adipocytes and then treated with Rimonabant (>1 µM) were more efficient substrates for exogenously added HSL compared to control LD. The CB1R-independent lipolysis was also demonstrated in primary adipocytes from fed rats which had been treated with a single dose of Rimonabant (30 mg/kg). (4) Conclusions: These data argue for interaction of Rimonabant (at high concentrations) with both the LD surface and the CB1R of primary rat adipocytes, each leading to increased access of HSL to LD in phosphorylation-independent and dependent fashion, respectively. Both mechanisms may lead to direct and acute stimulation of lipolysis at peripheral tissues upon Rimonabant administration and represent targets for future obesity therapy which do not encompass the hypothalamic CB1R.
Highlights
Lipid messengers of the endocannabinoid class play a crucial role in body weight control through engagement of several centrally and peripherally operating molecular mechanisms that coordinate the maintenance of energy homeostasis
(4) Conclusions: These data argue for interaction of Rimonabant with both the lipid droplets (LD) surface and the CB1R of primary rat adipocytes, each leading to increased access of hormone-sensitive lipase (HSL) to LD in phosphorylation-independent and dependent fashion, respectively
The fatty acids (FA)/glycerol ratio of around two at each concentration indicated considerable re-esterification operating in adipocytes under these conditions, the degree to which is apparently not affected by Rimonabant
Summary
Lipid messengers of the endocannabinoid class play a crucial role in body weight control through engagement of several centrally and peripherally operating molecular mechanisms that coordinate the maintenance of energy homeostasis (for a review see [1]). Endocannabinoids were thought to act exclusively or at least predominantly through the brain via binding to the G-protein-coupled cannabinoid type 1 and 2 receptors (CB1/2R) in the hypothalamus [2]. Rimonabant, named SR141716A by the original manufacturer, leads to considerable lowering of the body weight in laboratory animals and obese patients [5]. Cannabinoid research of the past two decades has considered the involvement of additional or alternative targets and mechanisms operating at peripheral tissues rather than the brain and mediating or contributing to the endocannabinoid-controlled regulation of the feeding behavior and whole body energy metabolism
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