Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice

Hiroshi Tsuneki*, Emi Tokai, Yuya Nakamura, Keisuke Takahashi, Mikio Fujita, Takehiro Asaoka, Kanta Kon, Yuuki Anzawa, Tsutomu Wada, Ichiro Takasaki, Kumi Kimura, Hiroshi Inoue, Masashi Yanagisawa, Takeshi Sakurai, Toshiyasu Sasaoka

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

61 被引用数 (Scopus)

抄録

Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wildtype mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver. Acknowledgments.

本文言語英語
ページ(範囲)459-470
ページ数12
ジャーナルDiabetes
64
2
DOI
出版ステータス出版済み - 2015/02/01

ASJC Scopus 主題領域

  • 内科学
  • 内分泌学、糖尿病および代謝内科学

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