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

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.