Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding.
Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding.
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DOI：
10.1172/jci.insight.164921
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发表时间：
2023-05-22
期刊：
影响因子：
8
通讯作者：
Reimann, Frank
中科院分区：
文献类型：
--
作者：
Adriaenssens, Alice;Broichhagen, Johannes;de Bray, Anne;Ast, Julia;Hasib, Annie;Jones, Ben;Tomas, Alejandra;Burgos, Natalie Figueredo;Woodward, Orla;Lewis, Jo;O'Flaherty, Elisabeth;El, Kimberley;Cui, Canqi;Harada, Norio;Inagaki, Nobuya;Campbell, Jonathan;Brierley, Daniel;Hodson, David J.;Samms, Ricardo;Gribble, Fiona;Reimann, Frank
中枢葡萄糖依赖的促胰岛素多肽受体(GIPR)信号转导通路在GIP治疗药物降低体重的能力中起着关键作用，但GIPR药理在脑内发挥作用的途径仍不完全清楚。我们探索了GIPR神经元在下丘脑和背侧迷走神经复合体(DVC)-大脑区域中的作用，这些区域对控制能量平衡至关重要。下丘脑GIPR的表达不是GIPR/GLP-1R协同作用所必需的。当化学刺激下丘脑和DVC GIPR神经元时，DVC GIPR神经元的激活减少了行走活动和诱导条件性味觉回避，而短效GIPR激动剂(GIPRA)则没有作用。在DVC内，孤束核(NTS)的GIPR神经元投射到远端脑区域，而不是最后区(AP)，在转录水平上是不同的。外周剂量的荧光GIPRA显示，通路仅限于中枢神经系统的脑室周围器官。这些数据表明，下丘脑、AP和NTS中的GIPR神经元在连接性、转录特征、外周可及性和食欲控制机制方面存在差异。这些结果突显了中枢GIPR信号轴的异质性，并建议研究GIP药理对摄食行为的影响应考虑多个调节途径的相互作用。
Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics’ ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) — brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
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
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.5
作者：
Ciofi, Philippe
通讯作者：
Ciofi, Philippe
影响因子：
3.1
作者：
Kastin, AJ;Akerstrom, V;Pan, WH
通讯作者：
Pan, WH