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

Abstract

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)

Melanin-Concentrating Hormone acts through hypothalamic kappa opioid system and p70S6K to stimulate acute food intake

“…Adult (8-10 weeks old) wild type (WT) C57BL6 mice, mutant mice (Oprk1 -/-) that lack functional k-OR subtype 1 (B6.129S2-Oprk1 tm1kff /J, The Jackson Laboratory) (Imbernon et al, 2016;Romero-Picó et al, 2013), were maintained on an ad libitum chow diet in Specific Pathogen Free (SPF) conditions and housed with a 12:12-h light-dark cycle. For surgery, mice were anesthetized by an intraperitoneal injection of 138 mg ketamine/Kg BW + 7 mg xylacine/Kg BW.…”

“…Central administration (Qu et al, 1996), or transgenic overexpression (Ludwig et al, 2001) of MCH increases food intake, whereas deletion of MCH (Alon and Friedman, 2006;Shimada et al, 1998) or its receptor (Chen et al, 2002) reduces body weight. In addition, MCH can modulate glucose metabolism (Kong et al, 2010;Ludwig et al, 2001) and peripheral lipid metabolism in the white adipose tissue (Imbernon et al, 2013) and liver (Imbernon et al, 2016;Pissios et al, 2006). Although it is well recognized that MCH acts in a way to preserve energy, the molecular mechanisms underlying MCH action are poorly understood.…”

“…A potential interaction among MCH and the opioid system to regulate food intake and food addiction was postulated previously (Lopez et al, 2011), but the mechanistic aspects and the specific brain areas where this interaction occurs remain unexplored. Since LHA seems to be a link between homeostatic and hedonic centers controlling feeding behavior, and k-OR co-localizes with MCH receptor in the LHA (Imbernon et al, 2016), we investigated whether MCH may act via the opioid system within this hypothalamic area to drive acute food consumption.…”

p107 Deficiency Increases Energy Expenditure by Inducing Brown‐Fat Thermogenesis and Browning of White Adipose Tissue

“…Western blots were performed as previously described Briefly, total protein samples (20 µg) prepared from a whole‐cell lysate of each tissue sample were subjected to SDS‐PAGE, electrotransferred onto an Immun‐Blot polyvinylidene difluoride membrane (Bio‐Rad, USA), and probed with antibodies against FAS (H‐300) (sc‐20140), PGC1α (sc‐13067), and PPARγ (sc‐7273) (Santa Cruz Biotechnology, USA); β 3 ‐AdR (ab694506), Cide‐A (ab8402), FGF21 (ab171941), HSL/LIPE (ab45422), PRDM16 (ab106410), and UCP1 (ab10983) (Abcam, USA); phospo‐HSL (Ser660) (#4126) (Cell Signaling Technology, USA); p107 (abcam ab245); vinculin (clone hVIN‐1) (Sigma‐Aldrich cat#V9131); GAPDH (CB1001) (Millipore, USA).…”

The Regulation of Lipid Metabolism by Targeting Opioid Receptors in Nonalcoholic Fatty Liver Disease

“…The activation of MOR with peripheral MOR agonist can prevent acute hepatic inflammation and cell death induced by hepatotoxin [40] . The overexpression of KOR in lateral hypothalamic area (LHA) can induce hepatic steatosis via parasympathetic nervous system to regulate lipid metabolism, but silencing of KOR expression can abolish hepatic steatosis [41] . The attenuation of KOR expression can decrease hepatic triglyceride synthesis in mice fed with high-energy diet (HED) [42] .…”