title: Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism.
abstract: Therapeutics aimed at blocking the cannabinoid 1 (CB1) receptor for treatment of obesity resulted in significant improvements in liver function, glucose uptake and pancreatic β-cell function independent of weight loss or CB1 receptor blockade in the brain, suggesting that peripherally-acting only CB1 receptor blockers may be useful therapeutic agents. Neuropsychiatric side effects and lack of tissue specificity precluded clinical use of first-generation, centrally acting CB1 receptor blockers. In this study we specifically analyzed the potential relevance to diabetes of human CB1 receptor isoforms in extraneural tissues involved in glucose metabolism. We identified an isoform of the human CB1 receptor (CB1b) that is highly expressed in β-cells and hepatocytes but not in the brain. Importantly, CB1b shows stronger affinity for the inverse agonist JD-5037 than for rimonabant compared to CB1 full length. Most relevant to the field, CB1b is a potent regulator of adenylyl cyclase activity in peripheral metabolic tissues. CB1b blockade by JD-5037 results in stronger adenylyl cyclase activation compared to rimonabant and it is a better enhancer of insulin secretion in β-cells. We propose this isoform as a principal pharmacological target for the treatment of metabolic disorders involving glucose metabolism.
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Isabel
authors.initials: I
authors.lastname: González-Mariscal
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Krzysik-Walker
authors.affiliation: Department of Medicine, Johns Hopkins Medical Institutes, Baltimore, MD 21224, USA.
authors.forename: Máire E
authors.initials: ME
authors.lastname: Doyle
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Liu
authors.affiliation: Department of Medicine, Johns Hopkins Medical Institutes, Baltimore, MD 21224, USA.
authors.forename: Raffaello
authors.initials: R
authors.lastname: Cimbro
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Santa-Cruz Calvo
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Soumita
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Cieśla
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Olga D
authors.initials: OD
authors.lastname: Carlson
authors.affiliation: Thermo Fisher Scientific, 7300 Governor's Way, Frederick, MD 21704 USA.
authors.forename: Rafal P
authors.initials: RP
authors.lastname: Witek
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: O'Connell
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D020869:Gene Expression Profiling / Q000379:methods; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008659:Metabolic Diseases / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D017386:Sequence Homology, Amino Acid; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007328:Insulin; D010880:Piperidines; D020033:Protein Isoforms; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D013449:Sulfonamides; C577200:JD5037; D005947:Glucose; D000077285:Rimonabant