CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance

  1. Adi Drori
  2. Asaad Gammal
  3. Shahar Azar
  4. Liad Hinden
  5. Rivka Hadar
  6. Daniel Wesley
  7. Alina Nemirovski
  8. Gergő Szanda
  9. Maayan Salton
  10. Boaz Tirosh
  11. Joseph Tam  Is a corresponding author
  1. The Hebrew University of Jerusalem, Israel
  2. National Institute on Alcohol Abuse & Alcoholism, United States
  3. Semmelweis University, Hungary
  4. Hebrew University of Jerusalem, Israel

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) 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

Article and author information

Author details

  1. Adi Drori

    Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Asaad Gammal

    Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Shahar Azar

    Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Liad Hinden

    Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0307-4350
  5. Rivka Hadar

    Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel Wesley

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse & Alcoholism, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Alina Nemirovski

    Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Gergő Szanda

    Department of Physiology, Semmelweis University, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  9. Maayan Salton

    Biochemistry and molecular biology, Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Boaz Tirosh

    The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8067-6577
  11. Joseph Tam

    Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
    For correspondence
    yossit@ekmd.huji.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0948-0093

Funding

Israel Science Foundation (617/14)

  • Joseph Tam

Israel Science Foundation (158/18)

  • Joseph Tam

The Obesity Society's Early Career Research Award

  • Joseph Tam

ERC-2015-StG grant (676841)

  • Joseph Tam

Hungarian National Research, Development, and Innovation Office (NKFI-6/FK_124038)

  • Gergő Szanda

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal studies were approved by the Institutional Animal Care and Use Committee of the Hebrew University of Jerusalem (AAALAC accreditation #1285; Ethic approval numbers MD-14-14008 & MD-19-15951). Animal studies are reported in compliance with the ARRIVE guidelines (Kilkenny et al., 2010), and are based on the rule of the replacement, refinement, or reduction. All the animals used in this study were housed under specific pathogen‐free (SPF) conditions, up to five per cage, in standard plastic cages with natural soft sawdust as bedding. The animals were maintained under controlled temperature of 22-24{degree sign}C, humidity at 55 {plus minus} 5%, and alternating 12-hour light/dark cycles (lights were on between 7:00 and 19:00 hr), and provided with food and water ad libitum.

Reviewing Editor

  1. Anna Mae Diehl, Duke University School of Medicine, United States

Publication history

  1. Received: July 6, 2020
  2. Accepted: November 17, 2020
  3. Accepted Manuscript published: November 19, 2020 (version 1)
  4. Version of Record published: December 10, 2020 (version 2)

Copyright

© 2020, Drori et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Adi Drori
  2. Asaad Gammal
  3. Shahar Azar
  4. Liad Hinden
  5. Rivka Hadar
  6. Daniel Wesley
  7. Alina Nemirovski
  8. Gergő Szanda
  9. Maayan Salton
  10. Boaz Tirosh
  11. Joseph Tam
(2020)
CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance
eLife 9:e60771.
https://doi.org/10.7554/eLife.60771
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