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CB1R Regulates Soluble Leptin Receptor Levels via CHOP, Contributing to Hepatic Leptin Resistance

Adi Drori, Asaad Gammal, Shahar Azar, Liad Hinden, Rivka Hadar, Daniel Wesley, Alina Nemirovski, Gergő Szanda, Maayan Salton, View ORCID ProfileBoaz Tirosh, View ORCID ProfileJoseph Tam
doi: https://doi.org/10.1101/2020.07.14.202283
Adi Drori
1Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
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Asaad Gammal
1Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
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Shahar Azar
1Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
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Liad Hinden
1Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
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Rivka Hadar
1Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
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Daniel Wesley
2Laboratory of Physiological Studies, National Institute on Alcohol Abuse & Alcoholism, Bethesda, MD USA
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Alina Nemirovski
1Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
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Gergő Szanda
3MTA-SE Laboratory of Molecular Physiology, Department of Physiology, Semmelweis University, Budapest, Hungary
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Maayan Salton
4Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Israel
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Boaz Tirosh
5The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
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  • ORCID record for Boaz Tirosh
Joseph Tam
1Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
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  • ORCID record for Joseph Tam
  • For correspondence: yossit@ekmd.huji.ac.il
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Abstract

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) contributes to hyperleptinemia and leptin resistance, effects that are known to be regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade as well as genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and consequently hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, fat mass, dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in 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 involves in the development of hepatic leptin resistance by regulating sOb-R levels via CHOP.

Summary Here we describe a novel molecular aspect by which the hepatic endocannabinoid/CB1R system contributes to hepatic leptin resistance by regulating soluble leptin receptor levels via CHOP.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 14, 2020.
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CB1R Regulates Soluble Leptin Receptor Levels via CHOP, Contributing to Hepatic Leptin Resistance
Adi Drori, Asaad Gammal, Shahar Azar, Liad Hinden, Rivka Hadar, Daniel Wesley, Alina Nemirovski, Gergő Szanda, Maayan Salton, Boaz Tirosh, Joseph Tam
bioRxiv 2020.07.14.202283; doi: https://doi.org/10.1101/2020.07.14.202283
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CB1R Regulates Soluble Leptin Receptor Levels via CHOP, Contributing to Hepatic Leptin Resistance
Adi Drori, Asaad Gammal, Shahar Azar, Liad Hinden, Rivka Hadar, Daniel Wesley, Alina Nemirovski, Gergő Szanda, Maayan Salton, Boaz Tirosh, Joseph Tam
bioRxiv 2020.07.14.202283; doi: https://doi.org/10.1101/2020.07.14.202283

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