The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide.
The role of nausea in food intake and body weight suppression by peripheral GLP-1 receptor agonists, exendin-4 and liraglutide.
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DOI：
10.1016/j.neuropharm.2011.12.022
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发表时间：
2012-04
影响因子：
4.7
通讯作者：
Hayes MR
中科院分区：
文献类型：
--
作者：
Kanoski SE;Rupprecht LE;Fortin SM;De Jonghe BC;Hayes MR
FDA批准的胰高血糖素样肽-1受体（GLP-1 R）激动剂exendin-4和利拉鲁肽可降低摄食量和体重。恶心是这些GLP-1 R激动剂报告的最常见不良副作用。尚不清楚exendin-4和利拉鲁肽是否独立于恶心发生摄食抑制。此外，对介导与外周GLP-1 R激动剂使用相关的恶心的神经生理学机制知之甚少。使用两种已建立的啮齿类动物恶心模型[条件性味觉回避（CTA）和异食癖（摄入非营养物质）]，结果表明，抑制摄食量的所有外周剂量的毒蜥外泌肽-4也会产生CTA，而一剂利拉鲁肽可抑制摄食量而不产生CTA。毒蜥外泌肽-4长期（12天）每日外周给药导致异食癖逐渐增加，同时伴有稳定、持续的摄食量和体重抑制，而每日利拉鲁肽的异食癖反应和摄食量减少更为短暂。结果表明，伴随外周毒蜥外泌肽-4的恶心反应通过涉及脑中GLP-1 R激活的迷走神经非依赖性途径发生，因为与GLP-1 R拮抗剂毒蜥外泌肽-（9-39）CNS联合给药可减弱毒蜥外泌肽-4诱导的异食癖反应，但迷走神经切断术不会减弱。将毒蜥外泌肽-4直接给予孤束核（mNTS）内侧亚核，而不是杏仁核中央核，减少了摄食量并产生异食癖反应，确立mNTS是介导GLP-1 R激动剂相关恶心反应的潜在GLP-1 R表达部位。
The FDA-approved glucagon-like-peptide-1 receptor (GLP-1R) agonists exendin-4 and liraglutide reduce food intake and body weight. Nausea is the most common adverse side effect reported with these GLP-1R agonists. Whether food intake suppression by exendin-4 and liraglutide occurs independently of nausea is unknown. Further, the neurophysiological mechanisms mediating the nausea associated with peripheral GLP-1R agonist use are poorly understood. Using two established rodent models of nausea [conditioned taste avoidance (CTA) and pica (ingestion of non-nutritive substances)], results show that all peripheral doses of exendin-4 that suppress food intake also produce CTA, whereas one dose of liraglutide suppresses intake without producing CTA. Chronic (12 days) daily peripheral administration of exendin-4 produces a progressive increase in pica coupled with stable, sustained food intake and body weight suppression, whereas the pica response and food intake reduction by daily liraglutide are more transient. Results demonstrate that the nausea response accompanying peripheral exendin-4 occurs via a vagal-independent pathway involving GLP-1R activation in the brain as the exendin-4-induced pica response is attenuated with CNS co-administration of the GLP-1R antagonist exendin-(9-39), but not by vagotomy. Direct administration of exendin-4 to the medial subnucleus of the nucleus tractus solitarius (mNTS), but not to the central nucleus of the amygdala, reduced food intake and produced a pica response, establishing the mNTS as a potential GLP-1R-expressing site mediating nausea responses associated with GLP-1R agonists.
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影响因子：
2.9
作者：
Hayes, Matthew R.;De Jonghe, Bart C.;Kanoski, Scott E.
通讯作者：
Kanoski, Scott E.
影响因子：
5.8
作者：
Blonde, L.;Klein, E. J.;Kendall, D. M.
通讯作者：
Kendall, D. M.
影响因子：
29
作者：
Hayes, Matthew R.;Leichner, Theresa M.;Bence, Kendra K.
通讯作者：
Bence, Kendra K.
影响因子：
2.9
作者：
de Jonghe, Bart C.;Lawler, Maureen P.;Horn, Charles C.;Tordoff, Michael G.
通讯作者：
Tordoff, Michael G.
DOI：
10.1111/j.1463-1326.2010.01356.x
发表时间：
2011-04
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Garber A;Henry RR;Ratner R;Hale P;Chang CT;Bode B;LEAD-3 (Mono) Study Group
通讯作者：
LEAD-3 (Mono) Study Group