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.
Bibliographical noteFunding Information:
This study was supported by grants from the Israeli Science Foundation (ISF; 617/14 and 158/18), The Obesity Society?s Early Career Research Award, and an ERC-2015-StG grant (#676841) to J.T, as well as the Hungarian National Research, Development, and Innovation Office (Grant #NKFI-6/ FK_124038 to G.S.). This paper is dedicated to the memory of Simon Tam. Israel Science Foundation 617/14 Joseph Tam Israel Science Foundation 158/18 Joseph Tam Obesity Society Early Career Research Award Joseph Tam ERC-2015-StG grant 676841 Joseph Tam Hungarian National Research, Development, and Innovation Office NKFI-6/FK_124038 Gerg? Szanda The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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