Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation.
Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation.
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DOI：
10.1016/j.molmet.2021.101407
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发表时间：
2022-01
影响因子：
8.1
通讯作者：
D'Agostino G
中科院分区：
文献类型：
--
作者：
Costa A;Ai M;Nunn N;Culotta I;Hunter J;Boudjadja MB;Valencia-Torres L;Aviello G;Hodson DJ;Snider BM;Coskun T;Emmerson PJ;Luckman SM;D'Agostino G
胰高血糖素样肽-1受体激动剂（GLP-1 RA）是降低食欲和体重的有效药物。这些行动是中央介导的，然而，涉及的神经元基板知之甚少。我们在小鼠中采用神经解剖学、遗传学和行为学方法相结合的方法，研究尾侧脑干胆囊收缩素表达神经元参与GLP-1 RA exendin-4的作用。我们进一步证实了非人类灵长类动物大脑中的关键神经解剖学发现。我们发现，尾侧脑干中的胆囊收缩素表达神经元是GLP-1 RA的厌食和体重降低作用以及GLP-1 RA诱导的条件性味觉回避的诱导所必需的。我们进一步表明，虽然胆囊收缩素表达神经元不是葡萄糖依赖性促胰岛素肽（GIP）的直接靶点，但GIP受体激活导致这些GLP-1 RA反应神经元的招募减少，并选择性减少条件性味觉回避。除了揭示GLP-1 RA完全降低食欲和体重作用所需的神经元群体外，我们的数据还为理解和改善GLP-1 RA诱导的恶心（退出治疗的主要因素）提供了一个新的框架。CCKAP/NTS神经元是GLP-1受体激动剂的完全厌食和降低体重作用所必需的。GLP-1受体激动剂通过激活CCKAP/NTS神经元促进条件性味觉回避的形成。CCKAP/NTS神经元不响应于GIP受体激动剂而被激活。GIP受体激动剂减少尾侧脑干中GLP-1受体激动剂诱导的神经元反应。GIP受体激动剂减少GLP-1受体激动剂诱导的条件性味觉回避
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood. We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain. We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs and for the induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance. In addition to disclosing a neuronal population required for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea — a major factor for withdrawal from treatment. CCKAP/NTS neurons are required for the full anorectic and body weight-lowering effect of GLP-1 receptor agonists. GLP-1 receptor agonists promote the formation of conditioned taste avoidance by activating CCKAP/NTS neurons. CCKAP/NTS neurons are not activated in response to GIP receptor agonists. GIP receptor agonists reduce GLP-1 receptor agonist-induced neuronal responses in the caudal brainstem. GIP receptor agonists reduce GLP-1 receptor agonist-induced conditioned taste avoidance.
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影响因子：
7.7
作者：
Borner T;Geisler CE;Fortin SM;Cosgrove R;Alsina-Fernandez J;Dogra M;Doebley S;Sanchez-Navarro MJ;Leon RM;Gaisinsky J;White A;Bamezai A;Ghidewon MY;Grill HJ;Crist RC;Reiner BC;Ai M;Samms RJ;De Jonghe BC;Hayes MR
通讯作者：
Hayes MR
DOI：
10.1152/ajpregu.00179.2014
发表时间：
2014-08-15
影响因子：
2.8
作者：
Alhadeff, Amber L.;Grill, Harvey J.
通讯作者：
Grill, Harvey J.
影响因子：
4.8
作者：
Hayes, Matthew R.;Skibicka, Karolina P.;Grill, Harvey J.
通讯作者：
Grill, Harvey J.
影响因子：
158.5
作者：
Pi-Sunyer, Xavier;Astrup, Arne;Wilding, John P. H.
通讯作者：
Wilding, John P. H.
影响因子：
29
作者：
Hayes, Matthew R.;Leichner, Theresa M.;Bence, Kendra K.
通讯作者：
Bence, Kendra K.