The Cannabinoid CB1 Receptor Antagonist Rimonabant Stimulates 2-Deoxyglucose Uptake in Skeletal Muscle Cells by Regulating the Expression of Phosphatidylinositol-3-kinase

Esposito, Iolanda; Proto, Maria; Gazzerro, Patrizia; Laezza, Chiara; Miele, Claudia; Alberobello, Anna Teresa; D’Esposito, Vittoria; Béguinot, Francesco; Formisano, Pietro; Bifulco, Maurizio

doi:10.1124/mol.108.049205

Cited by 92 publications

(96 citation statements)

References 47 publications

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“…Our finding that acute agonism of CB1R impaired insulin-stimulated Akt phosphorylation is in agreement with several in vitro studies that have shown rapid effects of CB1R modulation on insulin signalling. For example, Esposito et al demonstrated that SR141716 stimulated 2-DG uptake in L6 cells through phosphatidylinositol 3-kinase and downstream proteins, including Akt, an effect observed as early as 30 min post treatment [46]. In human skeletal muscle cells, treatment with the CB1R agonist anandamide for 1 h increased ERK1/ 2 and p38 mitogen-activated protein kinase, and impaired insulin-stimulated phosphorylation of Akt (Ser473), but not of Akt (Thr308) [41].…”

Section: Discussionmentioning

confidence: 99%

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

et al. 2011

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Aims/hypothesis Modulation of central nervous system (CNS) and extra-CNS cannabinoid receptor type 1 (CB1R) affects metabolic conditions, independently of weight loss. Here we examined the relative contributions of acute CNS and extra-CNS CB1R modulation on insulin sensitivity using pharmacological gain-and loss-of-function of CB1R in mice. Methods We assessed the effects of acute modulation of CB1R on insulin sensitivity and tissue glucose uptake by administering a CB1R agonist (HU210) and antagonist (AM251) (vs vehicle) i.v. in wild-type mice. In addition, we administered a CB1R agonist (vs vehicle) systemically (i.v.) to Cb1r (also known as Cnr1) knockout (Cb1r −/− ) mice or intracerebroventricularly (i.c.v.) in wild-type mice to elucidate the peripheral vs CNS-mediated regulatory effect of CB1R on insulin sensitivity.Results HU210 induced significant insulin resistance in wild-type mice with a reduction of whole-body glucose disappearance rate and muscle Akt phosphorylation, as well as of glucose uptake by skeletal muscle, but not by adipose tissue, changes that were prevented by pretreatment with AM251. HU210 did not affect insulin sensitivity in Cb1r −/− mice, suggesting that the observed effects were mediated through CB1R. HU210 administered i.c.v. did not induce insulin resistance, suggesting that acute stimulation of CNS CB1R was not required for this effect. Conclusions/interpretation Skeletal muscle insulin sensitivity is affected by acute CB1R modulation. These changes are mediated by extra-CNS CB1R, probably by the receptors in skeletal muscle tissue.

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Section: Discussionmentioning

confidence: 99%

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

et al. 2011

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“…Akt activation by CB1 receptor antagonist rimonabant has been reported in L6 skeletal muscle cells and in mouse primary myocytes [4] . In these cells, rimonabant increased 2-deoxyglucose uptake, which was blunted by co-incubation with the PI3K inhibitor LY294002.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, CB1 blockade in adipose tissue induces decreased abdominal fat, increased adiponectin and HDL, decreased triglycerides (TG), low-density lipoprotein (LDL), C-reactive protein (CRP), decreased insulin resistance and glycosylated hemoglobin [1] . Rimonabant also stimulates 2-deoxyglucose uptake in skeletal muscle cells [4] .…”

Section: Introductionmentioning

confidence: 99%

Rimonabant inhibits TNF-α-induced endothelial IL-6 secretion via CB1 receptor and cAMP-dependent protein kinase pathway

et al. 2010

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Aim: To investigate whether rimonabant, a cannabinoid receptor antagonist , had inhibitory effects on inflammatory reactions in human umbilical vein endothelial cells (HUVEC). Methods: TNF-α-induced IL-6 production was measured by ELISA and effects on related signaling pathways were investigated by immunoblot analysis. Cellular cAMP level was measured using kinase-coupled luciferase reaction. Results: Rimonabant at 1 and 10 μmol/L significantly inhibited TNF-α-induced IL-6 production when added 15, 30 and 60 minutes before TNF-α treatment. Rimonabant also inhibited TNF-α-induced phosphorylation of IκB kinase (IKK) α/β and IκB-α degradation. ACEA, a cannabinoid receptor subtype 1 (CB1) agonist, added before rimonabant abolished the former effects of rimonabant. H-89, an inhibitor of cAMP-dependent protein kinase (PKA), abolished the inhibitory effects of rimonabant on TNF-α induced IL-6 production. Rimonabant also increased the phosphorylation of PKA regulatory subunit II (PKA-RII), implying the essential role of PKA activation in the inhibitory effects of rimonabant. Treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin did not abolish the inhibitory effects of rimonabant on TNF-α induced IL-6 production. Conclusion: Rimonabant had anti-inflammatory effects on endothelial cells and inhibited TNF-α-induced IKKα/β phosphorylation, IκB-α degradation and IL-6 production in HUVEC. This effect was related to CB1 antagonism and PKA activation.

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“…Muscle cells produce endocannabinoids and express cannabinoid receptors and metabolic enzymes (165, 234,249,483). In the skeletal muscle, CB1 activation by endocannabinoids plays a role in the development of insulin resistance, possibly by enhancing IRS-1 phosphorylation and ERK activation (234,483).…”

Section: Skeletal Musclementioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

380

337

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Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

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The Cannabinoid CB1 Receptor Antagonist Rimonabant Stimulates 2-Deoxyglucose Uptake in Skeletal Muscle Cells by Regulating the Expression of Phosphatidylinositol-3-kinase

Cited by 92 publications

References 47 publications

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

Rimonabant inhibits TNF-α-induced endothelial IL-6 secretion via CB1 receptor and cAMP-dependent protein kinase pathway

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

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