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Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress

The opioid system is widely known to modulate the brain reward system and thus affect the behavior of humans and other animals, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κ...

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Autores principales: Imbernon, Monica, Sanchez‐Rebordelo, Estrella, Romero‐Picó, Amparo, Kalló, Imre, Chee, Melissa J., Porteiro, Begoña, Al‐Massadi, Omar, Contreras, Cristina, Fernø, Johan, Senra, Ana, Gallego, Rosalia, Folgueira, Cintia, Seoane, Luisa M., van Gestel, Margriet, Adan, Roger A., Liposits, Zsolt, Dieguez, Carlos, López, Miguel, Nogueiras, Ruben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129461/
https://www.ncbi.nlm.nih.gov/pubmed/27387967
http://dx.doi.org/10.1002/hep.28716
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author Imbernon, Monica
Sanchez‐Rebordelo, Estrella
Romero‐Picó, Amparo
Kalló, Imre
Chee, Melissa J.
Porteiro, Begoña
Al‐Massadi, Omar
Contreras, Cristina
Fernø, Johan
Senra, Ana
Gallego, Rosalia
Folgueira, Cintia
Seoane, Luisa M.
van Gestel, Margriet
Adan, Roger A.
Liposits, Zsolt
Dieguez, Carlos
López, Miguel
Nogueiras, Ruben
author_facet Imbernon, Monica
Sanchez‐Rebordelo, Estrella
Romero‐Picó, Amparo
Kalló, Imre
Chee, Melissa J.
Porteiro, Begoña
Al‐Massadi, Omar
Contreras, Cristina
Fernø, Johan
Senra, Ana
Gallego, Rosalia
Folgueira, Cintia
Seoane, Luisa M.
van Gestel, Margriet
Adan, Roger A.
Liposits, Zsolt
Dieguez, Carlos
López, Miguel
Nogueiras, Ruben
author_sort Imbernon, Monica
collection PubMed
description The opioid system is widely known to modulate the brain reward system and thus affect the behavior of humans and other animals, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and adenoviral vectors overexpressing or silencing κOR were stereotaxically delivered in the lateral hypothalamic area (LHA) of rats. Vagal denervation was performed to assess its effect on liver metabolism. Endoplasmic reticulum (ER) stress was inhibited by pharmacological (tauroursodeoxycholic acid) and genetic (overexpression of the chaperone glucose‐regulated protein 78 kDa) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and western blot. We show that in the LHA κOR directly controls hepatic lipid metabolism through the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor 1 (MCH‐R1) in the LHA, and genetic disruption of κOR reduced melanin concentrating hormone–induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of κOR in the LHA attenuated both methionine choline–deficient, diet‐induced and choline‐deficient, high‐fat diet–induced ER stress, inflammation, steatohepatitis, and fibrosis, whereas overexpression of κOR in this area promoted liver steatosis. Overexpression of glucose‐regulated protein 78 kDa in the liver abolished hypothalamic κOR‐induced steatosis by reducing hepatic ER stress. Conclusions: This study reveals a novel hypothalamic–parasympathetic circuit modulating hepatic function through inflammation and ER stress independent of changes in food intake or body weight; these findings might have implications for the clinical use of opioid receptor antagonists. (Hepatology 2016;64:1086‐1104)
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spelling pubmed-51294612016-11-30 Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress Imbernon, Monica Sanchez‐Rebordelo, Estrella Romero‐Picó, Amparo Kalló, Imre Chee, Melissa J. Porteiro, Begoña Al‐Massadi, Omar Contreras, Cristina Fernø, Johan Senra, Ana Gallego, Rosalia Folgueira, Cintia Seoane, Luisa M. van Gestel, Margriet Adan, Roger A. Liposits, Zsolt Dieguez, Carlos López, Miguel Nogueiras, Ruben Hepatology Steatohepatitis/Metabolic Liver Disease The opioid system is widely known to modulate the brain reward system and thus affect the behavior of humans and other animals, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and adenoviral vectors overexpressing or silencing κOR were stereotaxically delivered in the lateral hypothalamic area (LHA) of rats. Vagal denervation was performed to assess its effect on liver metabolism. Endoplasmic reticulum (ER) stress was inhibited by pharmacological (tauroursodeoxycholic acid) and genetic (overexpression of the chaperone glucose‐regulated protein 78 kDa) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and western blot. We show that in the LHA κOR directly controls hepatic lipid metabolism through the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor 1 (MCH‐R1) in the LHA, and genetic disruption of κOR reduced melanin concentrating hormone–induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of κOR in the LHA attenuated both methionine choline–deficient, diet‐induced and choline‐deficient, high‐fat diet–induced ER stress, inflammation, steatohepatitis, and fibrosis, whereas overexpression of κOR in this area promoted liver steatosis. Overexpression of glucose‐regulated protein 78 kDa in the liver abolished hypothalamic κOR‐induced steatosis by reducing hepatic ER stress. Conclusions: This study reveals a novel hypothalamic–parasympathetic circuit modulating hepatic function through inflammation and ER stress independent of changes in food intake or body weight; these findings might have implications for the clinical use of opioid receptor antagonists. (Hepatology 2016;64:1086‐1104) John Wiley and Sons Inc. 2016-08-09 2016-10 /pmc/articles/PMC5129461/ /pubmed/27387967 http://dx.doi.org/10.1002/hep.28716 Text en © 2016 The Authors. (Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Steatohepatitis/Metabolic Liver Disease
Imbernon, Monica
Sanchez‐Rebordelo, Estrella
Romero‐Picó, Amparo
Kalló, Imre
Chee, Melissa J.
Porteiro, Begoña
Al‐Massadi, Omar
Contreras, Cristina
Fernø, Johan
Senra, Ana
Gallego, Rosalia
Folgueira, Cintia
Seoane, Luisa M.
van Gestel, Margriet
Adan, Roger A.
Liposits, Zsolt
Dieguez, Carlos
López, Miguel
Nogueiras, Ruben
Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress
title Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress
title_full Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress
title_fullStr Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress
title_full_unstemmed Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress
title_short Hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress
title_sort hypothalamic kappa opioid receptor mediates both diet‐induced and melanin concentrating hormone–induced liver damage through inflammation and endoplasmic reticulum stress
topic Steatohepatitis/Metabolic Liver Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129461/
https://www.ncbi.nlm.nih.gov/pubmed/27387967
http://dx.doi.org/10.1002/hep.28716
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