Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity

Hiroshi Tsuneki, Takahiro Maeda, Shinjiro Takata, Masanori Sugiyama, Koyuki Otsuka, Hinako Ishizuka, Yasuhiro Onogi, Emi Tokai, Chiaki Koshida, Kanta Kon, Ichiro Takasaki, Takeru Hamashima, Masakiyo Sasahara, Assaf Rudich, Daisuke Koya, Takeshi Sakurai, Masashi Yanagisawa, Akihiro Yamanaka, Tsutomu Wada, Toshiyasu Sasaoka

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish
Article number111497
Number of pages1
JournalCell Reports
Issue number3
StatePublished - 18 Oct 2022


  • autonomic nervous system
  • chronic inflammation
  • CP: Metabolism
  • endoplasmic reticulum stress
  • liver cancer
  • non-alcoholic fatty liver disease
  • non-alcoholic steatohepatitis
  • obesity
  • orexin/hypocretin
  • physical inactivity

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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