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

• Published in: Diabetologia Vol. 52; no. 4; pp. 664 - 674
• Main Authors: Eckardt, K, Sell, H, Taube, A, Koenen, M, Platzbecker, B, Cramer, A, Horrighs, A, Lehtonen, M, Tennagels, N, Eckel, J
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01-04-2009; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Adipocyte-conditioned medium; Adipocytes; Adipocytes - drug effects; Adipocytes - physiology; Adipose Tissue - drug effects; Adipose Tissue - physiology; Anandamide; Arachidonic Acids - pharmacology; Biological and medical sciences; Body fat; Cannabinoid Receptor Modulators - pharmacology; Cannabinoid receptor type 1; Cell Culture Techniques; Cell Differentiation; Diabetes; Diabetes. Impaired glucose tolerance; Endocannabinoids; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fundamental and applied biological sciences. Psychology; Glucose; Human Physiology; Human skeletal muscle cells; Humans; Insulin resistance; Insulin Resistance - physiology; Internal Medicine; Kinases; Ligands; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolic disorders; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - physiology; Musculoskeletal system; Obesity; Phosphorylation; Piperidines - pharmacology; Polyunsaturated Alkamides - pharmacology; Proteins; Pyrazoles - pharmacology; Receptor Cross-Talk - physiology; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - physiology; Rimonabant; Striated muscle. Tendons; Vertebrates: osteoarticular system, musculoskeletal system; Sweden; Germany; Rimonabant; Adipocyte-conditioned medium; Cannabinoid receptor type 1; Human skeletal muscle cells; Insulin resistance; Endocannabinoids; Anandamide; Endocrinopathy; Human; Adipocyte; Conditioned medium; Arachidonic acid derivatives; Diabetes mellitus; Metabolic diseases; Cannabinoid; Striated muscle; Target tissue resistance; Human skeletal muscle cells· Insulin resistance; Biological receptor
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-008-1240-4

Aims/hypothesis Cannabinoid type 1 receptor (CB1R) antagonists such as rimonabant (Rim) represent a novel approach to treat obesity and related metabolic disorders. Recent data suggest that endocannabinoids are also produced by human adipocytes. Here we studied the potential involvement of endocannabinoids in the negative crosstalk between fat and muscle. Methods The protein level of CB1R in human skeletal muscle cells (SkM) during differentiation was analysed using western blotting. SkM were treated with adipocyte-conditioned medium (CM) or anandamide (AEA) in combination with the CB1R antagonists Rim or AM251, and insulin-stimulated Akt phosphorylation and glucose uptake were determined. Furthermore, signalling pathways of CB1R were investigated. Results We revealed an increase of CB1R protein in SkM during differentiation. Twenty-four hour incubation of SkM with CM or AEA impaired insulin-stimulated Akt(Ser473) phosphorylation by 60% and up to 40%, respectively. Pretreatment of cells with Rim or AM251 reduced the effect of CM by about one-half, while the effect of AEA could be prevented completely. The reduction of insulin-stimulated glucose uptake by CM was completely prevented by Rim. Short-time incubation with AEA activated extracellular regulated kinase 1/2 and p38 mitogen-activated protein kinase, and impaired insulin-stimulated Akt(Ser473) phosphorylation, but had no effect on Akt(Thr308) and glycogen synthase kinase 3α/β phosphorylation. In addition, enhanced IRS-1 (Ser307) phosphorylation was observed. Conclusions/interpretation Our results show that the CB1R system may play a role in the development of insulin resistance in human SkM. The results obtained with CM support the notion that adipocytes may secrete factors which are able to activate the CB1R. Furthermore, we identified two stress kinases in the signalling pathway of AEA and enhanced IRS-1(Ser307) phosphorylation, potentially underlying the development of insulin resistance.