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

doi:10.1016/j.celrep.2022.111497

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 journal › Article › peer-review

9 Scopus citations

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.

Original language	English (US)
Article number	111497
Journal	Cell Reports
Volume	41
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2022.111497
State	Published - Oct 18 2022
Externally published	Yes

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.111497

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Tsuneki, H., Maeda, T., Takata, S., Sugiyama, M., Otsuka, K., Ishizuka, H., Onogi, Y., Tokai, E., Koshida, C., Kon, K., Takasaki, I., Hamashima, T., Sasahara, M., Rudich, A., Koya, D., Sakurai, T., Yanagisawa, M., Yamanaka, A., Wada, T., & Sasaoka, T. (2022). Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity. Cell Reports, 41(3), Article 111497. https://doi.org/10.1016/j.celrep.2022.111497

Tsuneki, H, Maeda, T, Takata, S, Sugiyama, M, Otsuka, K, Ishizuka, H, Onogi, Y, Tokai, E, Koshida, C, Kon, K, Takasaki, I, Hamashima, T, Sasahara, M, Rudich, A, Koya, D, Sakurai, T, Yanagisawa, M, Yamanaka, A, Wada, T & Sasaoka, T 2022, 'Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity', Cell Reports, vol. 41, no. 3, 111497. https://doi.org/10.1016/j.celrep.2022.111497

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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.",

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year = "2022",

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doi = "10.1016/j.celrep.2022.111497",

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T1 - Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity

AU - Tsuneki, Hiroshi

AU - Maeda, Takahiro

AU - Takata, Shinjiro

AU - Sugiyama, Masanori

AU - Otsuka, Koyuki

AU - Ishizuka, Hinako

AU - Onogi, Yasuhiro

AU - Tokai, Emi

AU - Koshida, Chiaki

AU - Kon, Kanta

AU - Takasaki, Ichiro

AU - Hamashima, Takeru

AU - Sasahara, Masakiyo

AU - Rudich, Assaf

AU - Koya, Daisuke

AU - Sakurai, Takeshi

AU - Yanagisawa, Masashi

AU - Yamanaka, Akihiro

AU - Wada, Tsutomu

AU - Sasaoka, Toshiyasu

PY - 2022/10/18

Y1 - 2022/10/18

N2 - 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.

AB - 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.

KW - CP: Metabolism

KW - autonomic nervous system

KW - chronic inflammation

KW - endoplasmic reticulum stress

KW - liver cancer

KW - non-alcoholic fatty liver disease

KW - non-alcoholic steatohepatitis

KW - obesity

KW - orexin/hypocretin

KW - physical inactivity

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SN - 2211-1247

VL - 41

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 111497

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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