PT - JOURNAL ARTICLE AU - Adi Drori AU - Asaad Gammal AU - Shahar Azar AU - Liad Hinden AU - Rivka Hadar AU - Daniel Wesley AU - Alina Nemirovski AU - Gergő Szanda AU - Maayan Salton AU - Boaz Tirosh AU - Joseph Tam TI - CB<sub>1</sub>R Regulates Soluble Leptin Receptor Levels via CHOP, Contributing to Hepatic Leptin Resistance AID - 10.1101/2020.07.14.202283 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.07.14.202283 4099 - http://biorxiv.org/content/early/2020/07/14/2020.07.14.202283.short 4100 - http://biorxiv.org/content/early/2020/07/14/2020.07.14.202283.full AB - 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 StatementThe authors have declared no competing interest.