Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

被引:62
作者
Tsuneki, Hiroshi [1 ]
Tokai, Emi [1 ]
Nakamura, Yuya [1 ]
Takahashi, Keisuke [1 ]
Fujita, Mikio [1 ]
Asaoka, Takehiro [1 ]
Kon, Kanta [1 ]
Anzawa, Yuuki [1 ]
Wada, Tsutomu [1 ]
Takasaki, Ichiro [2 ]
Kimura, Kumi [3 ]
Inoue, Hiroshi [3 ]
Yanagisawa, Masashi [4 ,5 ]
Sakurai, Takeshi [6 ]
Sasaoka, Toshiyasu [1 ]
机构
[1] Toyama Univ, Dept Clin Pharmacol, Toyama 930, Japan
[2] Toyama Univ, Div Mol Genet Res, Toyama 930, Japan
[3] Kanazawa Univ, Frontier Sci Org, Kanazawa, Ishikawa, Japan
[4] Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki, Japan
[5] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Howard Hughes Med Inst, Dallas, TX 75390 USA
[6] Kanazawa Univ, Fac Med, Dept Mol Neurosci & Integrat Physiol, Kanazawa, Ishikawa, Japan
基金
日本学术振兴会;
关键词
ENDOPLASMIC-RETICULUM STRESS; HIGH-FAT DIET; CIRCADIAN-RHYTHMS; GLUCOSE-HOMEOSTASIS; METABOLIC DISEASES; DIABETES-MELLITUS; ENERGY-METABOLISM; KNOCKOUT MICE; MOUSE-LIVER; RAT-BRAIN;
D O I
10.2337/db14-0695
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 para-sympathectomy, 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 459 appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver.
引用
收藏
页码:459 / 470
页数:12
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