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Müller, G. ; Herling, A.W.* ; Wied, S.* ; Müller, T.D.

CB1 receptor-dependent and independent induction of lipolysis in primary rat adipocytes by the inverse agonist rimonabant (SR141716A).

Molecules 25:896 (2020)
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Open Access Gold
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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.  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 mu M and after short-term incubation, partially additive to fi-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 mu M 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 mu M) 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cyclic Adenosine Monophosphate (camp)-dependent Signaling ; Cannabinoid Receptor 1 (cb1r) ; Hormone-sensitive Lipase (hsl) ; Interfacial Activation ; Lipid Droplets (ld) ; Lipolysis ; Obesity ; Rimonabant; Hormone-sensitive Lipase; Activated Protein-kinase; Brown Adipose-tissue; Diet-induced Obesity; Lipid Droplets; Cannabinoid Receptor; Endocannabinoid System; Monoglyceride Lipase; Adenylate-cyclase; Insulin
ISSN (print) / ISBN 1420-3049
e-ISSN 1420-3049
Journal Molecules
Quellenangaben Volume: 25, Issue: 4, Pages: , Article Number: 896 Supplement: ,
Publisher MDPI
Publishing Place Basel
Reviewing status Peer reviewed