Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake
Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake
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DOI：
10.1016/j.cmet.2019.07.013
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发表时间：
2019-11-05
期刊：
影响因子：
29
通讯作者：
Reimann, Frank
中科院分区：
文献类型：
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作者：
Adriaenssens, Alice E.;Biggs, Emma K.;Reimann, Frank
关于葡萄糖依赖性促胰岛素多肽（GIP）在肥胖症中的作用的模糊性来自于声称GIP受体（GIPR）激动和拮抗都是抑制体重增加的有效策略的相互矛盾的报道。为了能够鉴定和操纵Gipr表达（Gipr）细胞，我们创建了Gipr-Cre敲入小鼠。由于GIPR激动剂最近被报道抑制食物摄入，我们的目的是确定这种作用的中枢介质。在小鼠和人的弓状核、背内侧核和室旁核中鉴定出Gipr细胞，如通过RNAscope证实的。单细胞RNA测序鉴定了下丘脑Gipr细胞簇，其表现出血管、神经胶质和神经元细胞的转录组学特征，后者表达生长抑素，但几乎不表达阿黑皮素原或刺鼠相关肽。下丘脑Gipr细胞中Gq-DREADDs的激活抑制了体内摄食，这与伴随的GLP 1 R激活没有明显的相加作用。这些数据将下丘脑GIPR确定为调节能量平衡的靶点。
Ambiguity regarding the role of glucose-dependent insulinotropic polypeptide (GIP) in obesity arises from conflicting reports asserting that both GIP receptor (GIPR) agonism and antagonism are effective strategies for inhibiting weight gain. To enable identification and manipulation of Gipr-expressing (Gipr) cells, we created Gipr-Cre knockin mice. As GIPR-agonists have recently been reported to suppress food intake, we aimed to identify central mediators of this effect. Gipr cells were identified in the arcuate, dorsomedial, and paraventricular nuclei of the hypothalamus, as confirmed by RNAscope in mouse and human. Single-cellRNA-seq identified clusters of hypothalamic Gipr cells exhibiting transcriptomic signatures for vascular, glial, and neuronal cells, the latter expressing somatostatin but little pro-opiomelanocortin or agouti-related peptide. Activation of Gq-DREADDs in hypothalamic Gipr cells suppressed food intake in vivo, which was not obviously additive with concomitant GLP1R activation. These data identify hypothalamic GIPR as a target for the regulation of energy balance.