@article{0bb2a576e4f54606925c399dbcb4d47d,
title = "Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity",
abstract = "Non-alcoholic steatohepatitis (NASH) occasionally occurs under obesity; however, factors modulating the natural history of fatty liver disease remain unknown. Since hypothalamic orexin that regulates physical activity and autonomic balance prevents obesity, we investigate its role in NASH development. Male orexin-deficient mice fed a high-fat diet (HFD) show severe obesity and progression of NASH with fibrosis in the liver. Hepatic fibrosis also develops in ovariectomized orexin-deficient females fed an HFD but not ovariectomized wild-type controls. Moreover, long-term HFD feeding causes hepatocellular carcinoma (HCC) in orexin-deficient mice. Intracerebroventricular injection of orexin A or pharmacogenetic activation of orexin neurons acutely activates hepatic mTOR-sXbp1 pathway to prevent endoplasmic reticulum (ER) stress, a NASH-causing factor. Daily supplementation of orexin A attenuates hepatic ER stress and inflammation in orexin-deficient mice fed an HFD, and autonomic ganglionic blocker suppresses the orexin actions. These results suggest that hypothalamic orexin is an essential factor for preventing NASH and associated HCC under obesity.",
keywords = "CP: Metabolism, autonomic nervous system, chronic inflammation, endoplasmic reticulum stress, liver cancer, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, obesity, orexin/hypocretin, physical inactivity",
author = "Hiroshi Tsuneki and Takahiro Maeda and Shinjiro Takata and Masanori Sugiyama and Koyuki Otsuka and Hinako Ishizuka and Yasuhiro Onogi and Emi Tokai and Chiaki Koshida and Kanta Kon and Ichiro Takasaki and Takeru Hamashima and Masakiyo Sasahara and Assaf Rudich and Daisuke Koya and Takeshi Sakurai and Masashi Yanagisawa and Akihiro Yamanaka and Tsutomu Wada and Toshiyasu Sasaoka",
note = "Funding Information: This study was supported by JSPS KAKENHI grant numbers JP15K09380 (to H.T.), JP15K15599 (to T. Sasaoka), JP19H05011 (to T. Sasaoka), JP21K19704 (to H.T.), and JP22H03506 (to H.T.); JSPS and ISF under the Japan-Israel Research Cooperative Program (to T. Sasaoka); Toyama Pharmaceutical Valley Development Consortium (to T. Sasaoka); JST Moonshot R&D grant number JPMJMS2021 (to T. Sasaoka); JST SPRING grant number JPMJSP2145 (to T.M.); JST-the establishment of university fellowships toward the creation of science technology innovation grant number JPMJFS2115 (to M.S.); and Tamura Science and Technology Foundation (to T .Sasaoka). We thank Y. Nunome, T. Asaoka, Y. Matsuoka, T. Sekine, K. Honda, S. Masui, T. Matsushima, Dr. M. Nomoto, and Dr. K. Inokuchi (University of Toyama, Japan) for their technical assistance. Funding Information: This study was supported by JSPS KAKENHI grant numbers JP15K09380 (to H.T.), JP15K15599 (to T. Sasaoka), JP19H05011 (to T. Sasaoka), JP21K19704 (to H.T.), and JP22H03506 (to H.T.); JSPS and ISF under the Japan-Israel Research Cooperative Program (to T. Sasaoka); Toyama Pharmaceutical Valley Development Consortium (to T. Sasaoka); JST Moonshot R&D grant number JPMJMS2021 (to T. Sasaoka); JST SPRING grant number JPMJSP2145 (to T.M.); JST-the establishment of university fellowships toward the creation of science technology innovation grant number JPMJFS2115 (to M.S.); and Tamura Science and Technology Foundation (to T.Sasaoka). We thank Y. Nunome, T. Asaoka, Y. Matsuoka, T. Sekine, K. Honda, S. Masui, T. Matsushima, Dr. M. Nomoto, and Dr. K. Inokuchi (University of Toyama, Japan) for their technical assistance. Conceptualization and planning of experiments, H.T. and T. Sasaoka; methodology, A.R. D.K. T. Sakurai, M.Y. A.Y. and T.W.; investigation, T.M. S.T. M.S. K.O. H.I. Y.O. E.T. C.K. K.K. and I.T.; analysis, T.M. S.T. M.S. K.O. H.I. Y.O. C.K. K.K. I.T. T.H. and M. Sasahara; resources, T. Sakurai, M.Y. and A.Y.; writing, H.T. and T. Sasaoka. All authors edited the manuscript and approved the final manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = oct,
day = "18",
doi = "10.1016/j.celrep.2022.111497",
language = "English (US)",
volume = "41",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}