Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission
Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission
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DOI：
10.1038/s41467-020-17720-5
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发表时间：
2020-09-07
影响因子：
16.6
通讯作者：
Pers, Tune H.
中科院分区：
文献类型：
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作者：
Bentsen, Marie A.;Rausch, Dylan M.;Pers, Tune H.
在2型糖尿病（T2D）的啮齿动物模型中，单次脑室内注射成纤维细胞生长因子1 （FGF1）可诱导高血糖持续缓解，最近发现中基底下丘脑（MBH）是产生这种效果的脑区。为了更好地了解MBH中细胞对FGF1的反应，我们对糖尿病Lep（ob/ob）小鼠下丘脑的bbb79,000个单细胞转录组进行了测序，这些转录组是在icv注射FGF1或对照物后的第1天和第5天获得的。在不同的下丘脑细胞类型中观察到对FGF1的广泛转录反应，胶质细胞类型在两个时间点的反应都比神经元强得多。在第1天，细长细胞和室管膜细胞是对fgf1反应最强烈的细胞类型，但星形胶质细胞和少突胶质细胞谱系细胞随后变得更敏感。基于星形胶质细胞和Agrp神经元（黑素皮质素系统的关键组成部分）之间增强的细胞间相互作用的组织化学和超微结构证据，我们进行了一系列研究，表明完整的黑素皮质素信号传导是FGF1持续抗糖尿病作用所必需的。这些数据共同表明，下丘脑胶质细胞是FGF1作用的主要靶点，持续的糖尿病缓解依赖于完整的黑素皮质素信号传导。
In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lep(ob/ob) mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.