ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis.
ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis.
复制标题
DOI：
10.1007/s00125-023-06010-6
复制
发表时间：
2024-01
期刊：
影响因子：
8.2
通讯作者：
Davis, Autumn
中科院分区：
文献类型：
--
作者：
Chhabra, Kavaljit H.;Bathina, Siresha;Faniyan, Tumininu S.;Samuel, Dennis J.;Raza, Muhammad Ummear;Cordeiro, Leticia Maria de Souza;Di Prisco, Gonzalo Viana;Atwood, Brady K.;Robles, Jorge;Bainbridge, Lauren;Davis, Autumn
大脑是葡萄糖作为能量来源的主要消耗者，并调节全身葡萄糖以及能量平衡。虽然已知葡萄糖转运蛋白如GLUT 2和钠-葡萄糖协同转运蛋白2（SGLT 2）可调节葡萄糖稳态和代谢，但结合葡萄糖以激活大脑中葡萄糖信号通路的受体的身份尚不清楚。本研究的目的是在小鼠下丘脑中发现一种葡萄糖受体。在这里，我们使用高分子量的葡萄糖-生物素聚合物，通过基于细胞的亲和层析富集葡萄糖结合的小鼠下丘脑神经元。然后，我们对富集的神经元进行蛋白质组学分析，并将粘附G蛋白偶联受体1（ADGRL 1）鉴定为葡萄糖受体的最佳候选者。我们使用稳定表达人ADGRL 1的CHO细胞和配体-受体结合试验验证了葡萄糖-ADGRL 1相互作用。我们产生并确定了全球Adgrl 1基因敲除小鼠和下丘脑特异性Adgrl 1基因缺陷小鼠的表型。我们测量了这些小鼠中与葡萄糖和能量稳态相关的变量。我们还建立了一个Adgrl 1Cre小鼠模型，以研究ADGRL 1在电生理学检测葡萄糖中的作用。Adgrl 1在小鼠下丘脑腹内侧核（VMH）中高度表达。在小鼠VMH中缺乏Adgrl 1导致空腹高胰岛素血症，增强葡萄糖刺激的胰岛素分泌和胰岛素抵抗。此外，Adgrl 1缺陷小鼠对葡萄糖和禁食的摄食反应受损，伴异常葡萄糖感知，并在肥胖和高血糖症发生前减少体力活动。在雌性小鼠中，卵巢切除术是揭示ADGRL 1对能量和葡萄糖稳态的贡献所必需的。总之，我们的研究结果表明，ADGRL 1结合葡萄糖，并参与能量以及葡萄糖稳态的性别依赖性方式。靶向ADGRL 1可能会引入一类新的药物用于治疗2型糖尿病和肥胖症。本文的在线版本（10.1007/s 00125 -023-06010-6）包含同行评审但未经编辑的补充材料。
The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium−glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus. Here we used a high molecular mass glucose–biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose–ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand–receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. Adgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis. Altogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity. The online version of this article (10.1007/s00125-023-06010-6) contains peer-reviewed but unedited supplementary material.
登录
查看更多内容
影响因子：
16.2
作者：
Dhillon, H;Zigman, JM;Lowelll, BB
通讯作者：
Lowelll, BB
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
15.9
作者：
Flak, Jonathan N.;Goforth, Paulette B.;Myers, Martin G., Jr.
通讯作者：
Myers, Martin G., Jr.
影响因子：
3.7
作者：
Kinyua AW;Yang DJ;Chang I;Kim KW
通讯作者：
Kim KW
影响因子：
7.7
作者：
Henry FE;Sugino K;Tozer A;Branco T;Sternson SM
通讯作者：
Sternson SM