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

Citation:

A. Drori, A. Gammal, S. Azar, L. Hinden, R. Hadar, D. Wesley, A. Nemirovski, G. Szanda, M. Salton, B. Tirosh, and J. Tam. 2020. “Cb1r regulates soluble leptin receptor levels via chop, contributing to hepatic leptin resistance.” eLife, 9, Pp. 1-26.

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. © 2020, eLife Sciences Publications Ltd. All rights reserved.

Notes:

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See also: Joseph Tam
Last updated on 02/09/2021