Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle

Eckardt, Kristin; Sell, Henrike; Taube, Annika; Koenen, Marlis; Platzbecker, B.; Cramer, A.; Horrighs, A; Lehtonen, Marko; Tennagels, Norbert; Eckel, Jürgen

doi:10.1007/s00125-008-1240-4

Cited by 138 publications

(150 citation statements)

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“…Chronic, peripheral CB1R antagonism decreases hepatic glucose production, promotes lipid mobilisation independently of food intake and increases glucose utilisation in rats [20]. Recent in vitro data also suggest that adipocytes may secrete CB1R-activating factors and that CB1Rs in human skeletal muscle participate in the negative crosstalk between fat and muscle [41], with muscle CB1R playing a major role in the development of insulin resistance. Cb1r −/− mice do not develop hyperinsulinaemia, hyperleptinaemia and dyslipidaemic profile, even after chronic feeding with high-fat diet [11,21].…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown in vitro that insulin signalling may be affected by short-to long-term modulation of CB1R activity in muscle cells through differing mechanisms [41,45]. In L6 cells, 24 h activation of CB1R with N-(2-chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (ACEA) decreased signalling mediated by extracellular signalregulated protein kinase (ERK)1/2, but not signalling mediated by Akt, while antagonism with SR141716 increased Akt and ERK1/2 activation [45].…”

Section: Discussionmentioning

confidence: 99%

“…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]. These studies indicate that tonic modulation of CB1R can lead to changes in insulin action in muscle, possibly through the cross-talk between endocannabinoid system and insulin signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…They control systemic glucose and lipid metabolism, food intake, vascular homeostasis and immune response [10][11][12]. Among adipocyte secretory proteins and peptides are proinflammatory cytokines like IL-6 [13].…”

Section: Introductionmentioning

confidence: 99%

ER Stress in Adipocytes Inhibits Insulin Signaling, Represses Lipolysis, and Alters the Secretion of Adipokines Without Inhibiting Glucose Transport

Spinas

Nießen

2010

Horm Metab Res

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The endoplasmic reticulum (ER) is the intra-cellular site, where secreted and membrane proteins are synthesized. ER stress and activation of the unfolded protein response (UPR) contribute to insulin resistance and the development of diabetes in obesity. It was shown previously in hepatocytes that the UPR activates c-jun N-terminal kinase (JNK), which phosphorylates insulin receptor substrate (IRS) proteins on serine residues thereby inhibiting insulin signal transduction. Here we describe how ER stress affects insulin signaling and the biological function of adipocytes. In addition to inhibition of IRS we found that ER stress downregulates the expression of the insulin receptor. Concomitantly, insulininduced activation of Akt/PKB and of ERK1/2 was strongly inhibited. Ectopic expression of IRS1 or IRS2 strongly counteracted the inhibitory effect of ER stress on insulin signaling while pharmacological inhibition of JNK with SP600125 resulted only in a mild improvement. ER stress decreased the secretion of the adipokines adiponectin and leptin, but strongly increased secretion of IL-6. ER stress inhibited expression and insulin-induced phosphorylation of AS160, reduced lipolysis but did not inhibit glucose transport. Finally, supernatants collected from 3T3-L1 adipocytes undergoing ER stress improved or impaired proliferation when used to condition the culture medium of INS-1E beta-cells dependent on the degree of ER stress. It appears that ER stress in adipocytes might initially lead to changes resembling early prediabetic stages, which at least in part support the regulation of systemic energy homeostasis. ABSTRACTThe endoplasmic reticulum (ER) is the intra-cellular site, where secreted and membrane proteins are synthesized. ER stress and activation of the unfolded protein response (UPR) contribute to insulin resistance and the development of diabetes in obesity. It was shown previously in hepatocytes that the UPR activates c-jun N-terminal kinase (JNK) which phosphorylates insulin receptor substrate (IRS) proteins on serine residues thereby inhibiting insulin signal transduction. Here we describe how ER stress affects insulin signalling and the biological function of adipocytes. In addition to inhibition of IRS we found that ER stress downregulates the expression of the insulin receptor. Concomitantly, insulin-induced activation of Akt/PKB and of ERK1/2 was strongly inhibited. Ectopic expression of IRS1 or IRS2 strongly counteracted the inhibitory effect of ER stress on insulin signalling while pharmacological inhibition of JNK with SP600125 resulted only in a mild improvement. ER stress decreased the secretion of the adipokines adiponectin and leptin, but strongly increased secretion of IL-6. ER stress inhibited expression and insulin-induced phosphorylation of AS160, reduced lipolysis but did not inhibit glucose transport. Finally, supernatants collected from 3T3-L1 adipocytes undergoing ER stress improved or impaired proliferation when used to condition the culture medium of INS-1E -cells dependen...

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“…Both animal and human studies have linked the endocannabinoid system with food intake, lipogenesis and addictive behaviour (2). Furthermore, activation of the CB1 may play a role in the development of insulin resistance in skeletal muscle (3). In placebo-controlled clinical trials, treatment with the CB1-selective antagonist rimonabant has resulted in reduction in body weight and waist circumference and improvement of cardio-metabolic risk factors including insulin sensitivity and lipid profile (4)(5)(6)(7), and the appetite-suppressant effect of rimonabant has been shown to depend on CB1 (8).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

Frost

Nielsen²,

Wraae³

et al. 2010

European Journal of Endocrinology

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Objective: Both animal and human studies have associated the endocannabinoid system with obesity and markers of metabolic dysfunction. Blockade of the cannabinoid receptor 1 (CB1) caused weight loss and reduction in waist size in both obese and type II diabetics. Recent studies on common variants of the CB1 receptor gene (CNR1) and the link to obesity have been conflicting. The aim of the present study was to evaluate whether selected common variants of the CNR1 are associated with measures of obesity and fat distribution. Design and methods: The single nucleotide polymorphisms (SNPs) rs806381, rs10485179 and rs1049353 were genotyped, and body fat and fat distribution were assessed by the use of dual-energy X-ray absorptiometry and magnetic resonance imaging in a population-based study comprising of 783 Danish men, aged 20-29 years. Results: The rs806381 polymorphism was significantly associated with visceral fat mass (FM) only, whereas the rs1049353 was significantly and directly associated with visceral and intermuscular FM. None of the SNPs analysed were associated with total body FM or subcutaneous FM. Conclusion:The results point towards a link between common variants of the CNR1 and fat distribution in young men.

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Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle

Cited by 138 publications

References 48 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

ER Stress in Adipocytes Inhibits Insulin Signaling, Represses Lipolysis, and Alters the Secretion of Adipokines Without Inhibiting Glucose Transport

Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution

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