2. Academic Validation
  3. CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance

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

  • Elife. 2020 Nov 19;9:e60771. doi: 10.7554/eLife.60771.
Adi Drori 1,  Asaad Gammal 1,  Shahar Azar 1,  Liad Hinden 1,  Rivka Hadar 1,  Daniel Wesley 2,  Alina Nemirovski 1,  Gergő Szanda 3,  Maayan Salton 4,  Boaz Tirosh 5,  Joseph Tam 1
Affiliations

Affiliations

  • 1 Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
  • 2 Laboratory of Physiological Studies, National Institute on Alcohol Abuse & Alcoholism, Bethesda, United States.
  • 3 MTA-SE Laboratory of Molecular Physiology, Department of Physiology, Semmelweis University, Budapest, Hungary.
  • 4 Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, Jerusalem, Israel.
  • 5 The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
PMID: 33210603 DOI: 10.7554/eLife.60771
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.

Keywords

CHOP; ER stress; cb1 receptor; cell biology; endocannabinoids; leptin resistance; mouse; obesity.

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