Cargando…
Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism
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 CB...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027555/ https://www.ncbi.nlm.nih.gov/pubmed/27641999 http://dx.doi.org/10.1038/srep33302 |
_version_ | 1782454258945228800 |
---|---|
author | González-Mariscal, Isabel Krzysik-Walker, Susan M. Doyle, Máire E. Liu, Qing-Rong Cimbro, Raffaello Santa-Cruz Calvo, Sara Ghosh, Soumita Cieśla, Łukasz Moaddel, Ruin Carlson, Olga D. Witek, Rafal P. O’Connell, Jennifer F. Egan, Josephine M. |
author_facet | González-Mariscal, Isabel Krzysik-Walker, Susan M. Doyle, Máire E. Liu, Qing-Rong Cimbro, Raffaello Santa-Cruz Calvo, Sara Ghosh, Soumita Cieśla, Łukasz Moaddel, Ruin Carlson, Olga D. Witek, Rafal P. O’Connell, Jennifer F. Egan, Josephine M. |
author_sort | González-Mariscal, Isabel |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5027555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50275552016-09-22 Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism González-Mariscal, Isabel Krzysik-Walker, Susan M. Doyle, Máire E. Liu, Qing-Rong Cimbro, Raffaello Santa-Cruz Calvo, Sara Ghosh, Soumita Cieśla, Łukasz Moaddel, Ruin Carlson, Olga D. Witek, Rafal P. O’Connell, Jennifer F. Egan, Josephine M. Sci Rep Article 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. Nature Publishing Group 2016-09-19 /pmc/articles/PMC5027555/ /pubmed/27641999 http://dx.doi.org/10.1038/srep33302 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article González-Mariscal, Isabel Krzysik-Walker, Susan M. Doyle, Máire E. Liu, Qing-Rong Cimbro, Raffaello Santa-Cruz Calvo, Sara Ghosh, Soumita Cieśla, Łukasz Moaddel, Ruin Carlson, Olga D. Witek, Rafal P. O’Connell, Jennifer F. Egan, Josephine M. Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism |
title | Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism |
title_full | Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism |
title_fullStr | Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism |
title_full_unstemmed | Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism |
title_short | Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism |
title_sort | human cb1 receptor isoforms, present in hepatocytes and β-cells, are involved in regulating metabolism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027555/ https://www.ncbi.nlm.nih.gov/pubmed/27641999 http://dx.doi.org/10.1038/srep33302 |
work_keys_str_mv | AT gonzalezmariscalisabel humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT krzysikwalkersusanm humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT doylemairee humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT liuqingrong humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT cimbroraffaello humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT santacruzcalvosara humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT ghoshsoumita humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT cieslałukasz humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT moaddelruin humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT carlsonolgad humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT witekrafalp humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT oconnelljenniferf humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism AT eganjosephinem humancb1receptorisoformspresentinhepatocytesandbcellsareinvolvedinregulatingmetabolism |