title: Activation of type 2 cannabinoid receptors (CB2R) promotes fatty acid oxidation through the SIRT1/PGC-1α pathway.
abstract: Abnormal fatty acid oxidation has been associated with obesity and type 2 diabetes. At the transcriptional level, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) has been reported to strongly increase the ability of hormone nuclear receptors PPARα and ERRα to drive transcription of fatty acid oxidation enzymes. In this study, we report that a specific agonist of the type 2 cannabinoid receptor (CB2R) can lead to fatty acid oxidation through the PGC-1α pathway. We have found that CB2R is expressed in differentiated C2C12 myotubes, and that use of the specific agonist trans-caryophyllene (TC) stimulates sirtuin 1 (SIRT1) deacetylase activity by increasing the phosphorylation of cAMP response element-binding protein (CREB), thus leading to increased levels of PGC-1α deacetylation. This use of TC treatment increases the expression of genes linked to the fatty acid oxidation pathway in a SIRT1/PGC-1α-dependent mechanism and also drastically accelerates the rate of complete fatty acid oxidation in C2C12 myotubes, neither of which occur when CB2R mRNA is knocked down using siRNA. These results reveal that activation of CB2R by a selective agonist promotes lipid oxidation through a signaling/transcriptional pathway. Our findings imply that pharmacological manipulation of CB2R may provide therapeutic possibilities to treat metabolic diseases associated with lipid dysregulation.
authors.affiliation: Department of Endocrinology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Xuqin
authors.initials: X
authors.lastname: Zheng
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D000081223:Polycyclic Sesquiterpenes; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D018955:CD36 Antigens; D002227:Carbazoles; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000081223:Polycyclic Sesquiterpenes; C485290:Ppargc1a protein, mouse; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D012717:Sesquiterpenes; D015534:Trans-Activators; D014157:Transcription Factors; C024714:caryophyllene; D000242:Cyclic AMP; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Fatty acid oxidation; Peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α); Sirtuin 1 (Sirt1); Trans-caryophyllene; Type 2 cannabinoid receptor (CB2R)