{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T23:54:01Z","timestamp":1790553241434,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2016,8,9]],"date-time":"2016-08-09T00:00:00Z","timestamp":1470700800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:p>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 (\u03baOR) and adenoviral vectors overexpressing or silencing \u03baOR 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\u2010regulated protein 78 kDa) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and western blot. We show that in the LHA \u03baOR directly controls hepatic lipid metabolism through the parasympathetic nervous system, independent of changes in food intake and body weight. \u03baOR colocalizes with melanin concentrating hormone receptor 1 (MCH\u2010R1) in the LHA, and genetic disruption of \u03baOR reduced melanin concentrating hormone\u2013induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of \u03baOR in the LHA attenuated both methionine choline\u2013deficient, diet\u2010induced and choline\u2010deficient, high\u2010fat diet\u2013induced ER stress, inflammation, steatohepatitis, and fibrosis, whereas overexpression of \u03baOR in this area promoted liver steatosis. Overexpression of glucose\u2010regulated protein 78 kDa in the liver abolished hypothalamic \u03baOR\u2010induced steatosis by reducing hepatic ER stress. <jats:italic toggle=\"yes\">Conclusions<\/jats:italic>: This study reveals a novel hypothalamic\u2013parasympathetic 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. (H<jats:sc>epatology<\/jats:sc> 2016;64:1086\u20101104)<\/jats:p>","DOI":"10.1002\/hep.28716","type":"journal-article","created":{"date-parts":[[2016,7,7]],"date-time":"2016-07-07T22:52:57Z","timestamp":1467931977000},"page":"1086-1104","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":31,"title":["Hypothalamic kappa opioid receptor mediates both diet\u2010induced and melanin concentrating hormone\u2013induced liver damage through inflammation and endoplasmic reticulum stress"],"prefix":"10.1097","volume":"64","author":[{"given":"Monica","family":"Imbernon","sequence":"first","affiliation":[{"name":"Department of Physiology,CIMUS, University of Santiago de Compostela\u2010Instituto de Investigaci\u00f3n Sanitaria"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn),Santiago de Compostela,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estrella","family":"Sanchez\u2010Rebordelo","sequence":"additional","affiliation":[{"name":"Department of Physiology,CIMUS, University of Santiago de Compostela\u2010Instituto de Investigaci\u00f3n Sanitaria"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn),Santiago de Compostela,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amparo","family":"Romero\u2010Pic\u00f3","sequence":"additional","affiliation":[{"name":"Department of Physiology,CIMUS, University of Santiago de Compostela\u2010Instituto de Investigaci\u00f3n Sanitaria"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn),Santiago de Compostela,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imre","family":"Kall\u00f3","sequence":"additional","affiliation":[{"name":"Laboratory of Endocrine Neurobiology,Institute of Experimental Medicine, 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