A Major Role for Perifornical Orexin Neurons in the Control of Glucose Metabolism in Rats

被引:119
作者
Yi, Chun-Xia [1 ]
Serlie, Mireille J. [2 ]
Ackermans, Mariette T. [3 ]
Foppen, Ewout [1 ,2 ]
Buijs, Ruud M. [4 ]
Sauerwein, Hans P. [2 ]
Fliers, Eric [2 ]
Kalsbeek, Andries [1 ,2 ]
机构
[1] Netherlands Inst Neurosci, Dept Hypothalam Integrat Mech, Amsterdam, Netherlands
[2] Univ Amsterdam, Acad Med Ctr, Dept Endocrinol & Metab, NL-1105 AZ Amsterdam, Netherlands
[3] Univ Amsterdam, Acad Med Ctr, Dept Clin Chem, Lab Endocrinol, NL-1105 AZ Amsterdam, Netherlands
[4] Univ Nacl Autonoma Mexico, Inst Invest Biomed, Mexico City 04510, DF, Mexico
关键词
MELANIN-CONCENTRATING HORMONE; HEPATIC INSULIN-RESISTANCE; CENTRAL-NERVOUS-SYSTEM; NEUROPEPTIDE-Y; MEDIOBASAL HYPOTHALAMUS; SYMPATHETIC INNERVATION; PARAVENTRICULAR NUCLEUS; LATERAL HYPOTHALAMUS; HYPOCRETIN OREXIN; FEEDING-BEHAVIOR;
D O I
10.2337/db09-0385
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
OBJECTIVE-The hypothalamic neuropeptide orexin influences (feeding) behavior as well as energy metabolism. Administration of exogenous orexin-A into the brain has been shown to increase both food intake and blood glucose levels. In the present study, we investigated the role of endogenous hypothalamic orexin release in glucose homeostasis in rats. RESEARCH DESIGN AND METHODS-We investigated the effects of the hypothalamic orexin system on basal endogenous glucose production (EGP) as well as on hepatic and peripheral insulin sensitivity by changing orexinergic activity in the hypothalamus combined with hepatic sympathetic or parasympathetic denervation, two-step hyperinsulinemic-euglycemic clamps, immunohistochemistry, and RT-PCR studies. RESULTS-Hypothalamic disinhibition of neuronal activity by the gamma-aminobutyric acid receptor antagonist bicuculline (BIC) increased basal EGP, especially when BIC was administered in the perifornical area where orexin-containing neurons but not melanocortin-concentrating hormone-containing neurons were activated. The increased BIC-induced EGP was largely prevented by intracerebroventricular pretreatment with the orexin-1 receptor antagonist. Intracerebroventricular administration of orexin-A itself caused an increase in plasma glucose and prevented the daytime decrease of EGP. The stimulatory effect of intracerebroventricular orexin-A on EGP was prevented by hepatic sympathetic denervation. Plasma insulin clamped at two or six times the basal levels did not counteract the stimulatory effect of perifornical BIC on EGP, indicating hepatic insulin resistance. RT-PCR showed that stimulation of orexin neurons increased the expression of hepatic glucoregulatory enzymes. CONCLUSIONS-Hypothalamic orexin plays an important role in EGP, most likely by changing the hypothalamic output to the autonomic nervous system. Disturbance of this pathway may result in unbalanced glucose homeostasis. Diabetes 58:1998-2005, 2009
引用
收藏
页码:1998 / 2005
页数:8
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