CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance
The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-11-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/60771 |
| _version_ | 1811181017003720704 |
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| author | Adi Drori Asaad Gammal Shahar Azar Liad Hinden Rivka Hadar Daniel Wesley Alina Nemirovski Gergő Szanda Maayan Salton Boaz Tirosh Joseph Tam |
| author_facet | Adi Drori Asaad Gammal Shahar Azar Liad Hinden Rivka Hadar Daniel Wesley Alina Nemirovski Gergő Szanda Maayan Salton Boaz Tirosh Joseph Tam |
| author_sort | Adi Drori |
| collection | DOAJ |
| description | The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP. |
| first_indexed | 2024-04-11T09:11:16Z |
| format | Article |
| id | doaj.art-20e1152f591f43dbbde67febfde86193 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:11:16Z |
| publishDate | 2020-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-20e1152f591f43dbbde67febfde861932022-12-22T04:32:29ZengeLife Sciences Publications LtdeLife2050-084X2020-11-01910.7554/eLife.60771CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistanceAdi Drori0https://orcid.org/0000-0002-5790-9544Asaad Gammal1Shahar Azar2Liad Hinden3https://orcid.org/0000-0002-0307-4350Rivka Hadar4Daniel Wesley5Alina Nemirovski6Gergő Szanda7Maayan Salton8Boaz Tirosh9https://orcid.org/0000-0001-8067-6577Joseph Tam10https://orcid.org/0000-0002-0948-0093Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelObesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelObesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelObesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelObesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelLaboratory of Physiological Studies, National Institute on Alcohol Abuse & Alcoholism, Bethesda, United StatesObesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelMTA-SE Laboratory of Molecular Physiology, Department of Physiology, Semmelweis University, Budapest, HungaryDepartment of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, IsraelThe Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelObesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, IsraelThe soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.https://elifesciences.org/articles/60771endocannabinoidsleptin resistanceER stressobesitycb1 receptorCHOP |
| spellingShingle | Adi Drori Asaad Gammal Shahar Azar Liad Hinden Rivka Hadar Daniel Wesley Alina Nemirovski Gergő Szanda Maayan Salton Boaz Tirosh Joseph Tam CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance eLife endocannabinoids leptin resistance ER stress obesity cb1 receptor CHOP |
| title | CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance |
| title_full | CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance |
| title_fullStr | CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance |
| title_full_unstemmed | CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance |
| title_short | CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance |
| title_sort | cb1r regulates soluble leptin receptor levels via chop contributing to hepatic leptin resistance |
| topic | endocannabinoids leptin resistance ER stress obesity cb1 receptor CHOP |
| url | https://elifesciences.org/articles/60771 |
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