GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.
GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist-Induced Nausea and Emesis in Preclinical Models.
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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
胰高血糖素样肽1受体（GLP-1 R）激动剂可降低肥胖和糖尿病患者的体重并改善血糖控制。GLP-1治疗的患者依从性和最大疗效受到不良副作用的限制，包括恶心和呕吐。在三个不同的物种中（即，小鼠、大鼠和麝鼠），我们发现葡萄糖依赖性促胰岛素多肽受体（GIPR）信号传导阻断呕吐并减弱GLP-1 R激活引起的疾病行为，同时维持减少的食物摄入、体重减轻和改善的葡萄糖耐量。后脑的最后区和孤束核（AP/NTS）是GLP-1 R配体抑制摄食和体重以及处理呕吐刺激所必需的。使用单核RNA测序，我们鉴定了在不同的抑制性和兴奋性神经元群体上表达GIPR和GLP-1 R的AP/NTS细胞的细胞表型，其中GIPR在γ-氨基丁酸能神经元中的表达最高。这项工作表明，GLP-1 R和GIPR的组合药物靶向将通过减少恶心和呕吐来提高治疗肥胖和糖尿病的疗效。
Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in γ-aminobutyric acid-ergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.
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影响因子：
2.1
作者：
Ambati, S.;Duan, J.;Baile, C. A.
通讯作者：
Baile, C. A.
影响因子：
8.8
作者：
Borner, Tito;Workinger, Jayme L.;Doyle, Robert P.
通讯作者：
Doyle, Robert P.
影响因子：
4.8
作者：
Hayes, Matthew R.;Skibicka, Karolina P.;Grill, Harvey J.
通讯作者：
Grill, Harvey J.
DOI：
10.1111/dom.14089
发表时间：
2020-10
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Borner T;Shaulson ED;Tinsley IC;Stein LM;Horn CC;Hayes MR;Doyle RP;De Jonghe BC
通讯作者：
De Jonghe BC
影响因子：
4.7
作者：
Leon RM;Borner T;Stein LM;Urrutia NA;De Jonghe BC;Schmidt HD;Hayes MR
通讯作者：
Hayes MR