Peripheral and Central GLP-1 Receptor Populations Mediate the Anorectic Effects of Peripherally Administered GLP-1 Receptor Agonists, Liraglutide and Exendin-4
Peripheral and Central GLP-1 Receptor Populations Mediate the Anorectic Effects of Peripherally Administered GLP-1 Receptor Agonists, Liraglutide and Exendin-4
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DOI：
10.1210/en.2011-0174
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发表时间：
2011-08-01
期刊：
影响因子：
4.8
通讯作者：
Hayes, Matthew R.
中科院分区：
文献类型：
--
作者：
Kanoski, Scott E.;Fortin, Samantha M.;Hayes, Matthew R.
长效的高血糖素样多肽-1受体(GLP-1R)激动剂exendin-4和利拉鲁肽可以抑制食物摄入量和体重。这些GLP-1R激动剂外周给药所产生的厌食效应的中介部位(S)尚不清楚。实验探讨了ip给药后exendin-4和利拉鲁肽对食物摄取的抑制是否完全由外周GLP-1R介导，或者也涉及中枢神经系统(CNS)GLP-1R的直接激活。结果表明，中枢神经系统注射GLP-1R拮抗剂exendin-(9-39)(100 MU G)后，可减弱ip力拉鲁肽(10 MU G)和exendin-4(3 MU G)对GLP-1R的摄取抑制，尤其是在6h和24 h。对照实验表明，这些发现既不是基于GLP-1R拮抗剂作为非特异性竞争致氧信号的作用，也不是基于外周GLP-1R通过exendin-(9-39)外流到外周。为探讨隔下迷走神经传入上表达的GLP-1R在利拉鲁肽和exendin-4的厌食效应中的作用，比较了肌注激动剂后完全迷走神经传入大鼠和手术对照组大鼠的摄食量。利拉鲁肽和exendin-4对对照组大鼠在3h、6h和24h均有明显的摄食抑制作用，而对于隔膜下迷走神经去传入大鼠，需要更大剂量的GLP-1R激动剂才能显著抑制摄食，在利拉鲁肽后6h、24h和exendin-4后24h观察到这一现象。结论：外周给予Exendin-4和利拉鲁肽后，大鼠摄食抑制是通过激活迷走神经传入纤维上表达的GLP-1R和直接激活CNS GLP-1R实现的。(内分泌学152：3103-3112,2011)
The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after ip delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [ third intracerebroventricular (3(rd) ICV)] of the GLP-1R antagonist exendin-(9-39) (100 mu g), attenuated the intake suppression by ip liraglutide (10 mu g) and exendin-4 (3 mu g), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9-39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after ip delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4. Conclusion: Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation. (Endocrinology 152: 3103-3112, 2011)