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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 CB1 R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1 R 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 CB1 R 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.

Original languageAmerican English
Article numbere60771
Pages (from-to)1-26
Number of pages26
JournaleLife
Volume9
DOIs
StatePublished - Nov 2020

Bibliographical note

Funding Information:
This study was supported by grants from the Israeli Science Foundation (ISF; 617/14 and 158/18), The Obesity Society?s Early Career Research Award, and an ERC-2015-StG grant (#676841) to J.T, as well as the Hungarian National Research, Development, and Innovation Office (Grant #NKFI-6/ FK_124038 to G.S.). This paper is dedicated to the memory of Simon Tam. Israel Science Foundation 617/14 Joseph Tam Israel Science Foundation 158/18 Joseph Tam Obesity Society Early Career Research Award Joseph Tam ERC-2015-StG grant 676841 Joseph Tam Hungarian National Research, Development, and Innovation Office NKFI-6/FK_124038 Gerg? Szanda The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Publisher Copyright:
© 2020, eLife Sciences Publications Ltd. All rights reserved.

Fingerprint

Dive into the research topics of 'Cb1r regulates soluble leptin receptor levels via chop, contributing to hepatic leptin resistance'. Together they form a unique fingerprint.

Cite this