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

ELife
A. DroriJoseph Tam

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 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.

References

Dec 29, 1995·Cell·L A TartagliaR I Tepper
May 23, 1998·The Journal of Biological Chemistry·C LiJ M Friedman
Apr 24, 1999·Annals of Internal Medicine·C S Mantzoros
Jun 23, 2000·The Journal of Clinical Investigation·K El-HaschimiJ S Flier
Dec 5, 2000·The Journal of Biological Chemistry·L HuangC Li
May 15, 2001·Biochemical and Biophysical Research Communications·A LammertJ Kratzsch
Mar 26, 2002·Molecular and Cellular Endocrinology·Heather L Wilson, William J Roesler
May 15, 2002·The Biochemical Journal·Dipak P Ramji, Pelagia Foka
Jun 22, 2002·International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity·V OgierA Stricker-Krongrad
Oct 31, 2002·Nutrition Reviews·Gema Frühbeck
Mar 16, 2004·Molecular Endocrinology·Guoqing YangCai Li
Oct 16, 2004·Science·Umut OzcanGökhan S Hotamisligil
Jan 13, 2005·The Journal of Biological Chemistry·Paul CohenCai Li
Mar 29, 2005·Experimental Biology and Medicine·Ester FrideTim C Kirkham
Apr 21, 2005·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Palmiero MonteleoneVincenzo Di Marzo
Jul 6, 2005·International Journal of Obesity : Journal of the International Association for the Study of Obesity·T ReinehrW Andler
Jul 16, 2005·Annals of Medicine·Uberto PagottoRenato Pasquali
Sep 28, 2005·Diabetes·Stefan EngeliJens Jordan
Nov 25, 2005·Endocrine Reviews·Uberto PagottoRenato Pasquali
Dec 15, 2005·The Journal of Clinical Endocrinology and Metabolism·Katja SteinGerhard Jahreis
Apr 18, 2006·Cancer Cell·Arkaitz CarracedoGuillermo Velasco
May 4, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Motoyoshi EndoTomomi Gotoh
May 11, 2006·The Journal of Clinical Endocrinology and Metabolism·Isabel MatiasVincenzo Di Marzo
Jun 16, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Renato Malcher-LopesJeffrey G Tasker
Oct 27, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Cristina BlázquezManuel Guzmán
Mar 21, 2007·The Journal of Biological Chemistry·Céline JoussePierre Fafournoux
Jun 15, 2007·Nature Reviews. Molecular Cell Biology·David Ron, Peter Walter
Jul 20, 2007·Obesity·Yasuyo AriyamaMasatomo Mori
Mar 18, 2008·Molecular and Cellular Endocrinology·Isabel MatiasVincenzo Di Marzo
May 9, 2008·Journal of Neuroendocrinology·S Engeli
Jun 3, 2008·Nature Medicine·Christoph BuettnerChristoph Buettner
Aug 30, 2008·Molecular Pharmacology·Toru HosoiKoichiro Ozawa

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Citations

Oct 7, 2021·Diabetes & Metabolism Journal·Inês Sousa-LimaYoung-Bum Kim

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Methods Mentioned

BETA
transgenic
immunoprecipitation
ELISA
Protein Assay
PCR
Assay
ChIP

Software Mentioned

GraphPadPrism
ARRIVE

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