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Cb1r regulates soluble leptin receptor levels via chop, contributing to hepatic leptin resistance | School of Pharmacy

Cb1r regulates soluble leptin receptor levels via chop, contributing to hepatic leptin resistance

Citation:

Adi Drori, Gammal, Asaad , Azar, Shahar , Hinden, Liad , Hadar, Rivka , Wesley, Daniel , Nemirovski, Alina , Szanda, Gergő , Salton, Maayan , Tirosh, Boaz , and Tam, Joseph . 2020. “Cb1R Regulates Soluble Leptin Receptor Levels Via Chop, Contributing To Hepatic Leptin Resistance”. Elife, 9, Pp. 1–26. 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 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.