Hypothalamic kappa opioid receptor mediates both diet- and MCH-induced liver damage through inflammation and ER stress

Abstract

The opioid system is widely known to modulate the brain reward system and thus affect human and animal behaviour, 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 over-expressing 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. ER stress was inhibited by pharmacological (tauroursodeoxycholic acid - TUDCA) and genetic (over-expression of the chaperone glucose-regulated protein 78 kDa - GRP78) 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 via the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor (MCH-R1) in the LHA and genetic disruption of κOR reduced MCH-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- and choline deficient-high fat diet-induced ER stress, inflammation, steatohepatitis and fibrosis, whereas over-expression of κOR in this area promoted liver steatosis. Over-expression of the GRP78 in the liver abolished hypothalamic κOR-induced steatosis by reducing hepatic ER stress. CONCLUSIONS: Overall, this study reveals a novel hypothalamic-parasympathetic circuit modulating hepatic function via 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. This article is protected by copyright. All rights reserved