CB(1)R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance.

Citation:

Adi Drori, Asaad Gammal, Shahar Azar, Liad Hinden, Rivka Hadar, Daniel Wesley, Alina Nemirovski, Gergő Szanda, Maayan Salton, Boaz Tirosh, and Joseph Tam. 2020. “CB(1)R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance.” eLife, 9.

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)/CB(1)R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB(1)R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB(1)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 CB(1)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/CB(1)R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.