The D-Day of ghrelin.
The D-Day of ghrelin.
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Ghrelin的D日。
DOI：
10.1016/j.molmet.2016.05.007
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发表时间：
2016-07
影响因子：
8.1
通讯作者：
Mauvais-Jarvis F
中科院分区：
文献类型：
--
作者：
Tong J;Mauvais-Jarvis F
Ghrelin已成为葡萄糖稳态调节的重要参与者。在热量限制期间，酰基饥饿素（活性同种型）的存在对于防御低血糖和生存是必要的[1]。在禁食的人体中，生长激素释放肽给药可增强生长激素（GH）分泌，抑制胰岛素释放并促进胰岛素抵抗，以维持正常血糖[2]。生长激素释放肽的胰岛素抑制作用的确切机制尚不清楚。生长素释放肽主要由胃内分泌细胞分泌，尽管胰岛中的新型内分泌细胞类型（胰岛细胞）[3]也产生生长素释放肽，提高了胰岛内调节的可能性。Ghrelin已被证明可激活β细胞上的受体GH促分泌素受体（GHSR）1a，通过Gα i2信号通路抑制葡萄糖刺激的胰岛素分泌（GSIS）[4]，并直接作用于α细胞，通过升高细胞内钙和促进ERK磷酸化刺激胰高血糖素分泌[5]。β细胞胰岛素分泌的另一种主要抑制剂是通过SST受体亚型-5（SSTR 5）的生长抑素（SST）。Park及其同事报告了生长激素释放肽和SST通过INS-1 β细胞中的受体在低能量和高能量平衡状态下调节GSIS的协同作用[6]。胰岛细胞的紧密接近使得很难区分激素对β细胞的直接和间接作用。然而，分子遗传技术和下一代测序的最新进展允许对单个细胞中的基因表达进行无偏评估，并提供了一个独特的机会来拦截胰岛细胞之间的串扰。在本期《分子代谢》杂志中，DiBruccio et al. [7]报道了ghrelin通过直接作用于δ细胞促进SST释放的一种新的胰岛素抑制机制，尽管δ细胞是第三大最常见的胰岛细胞类型，但对调节δ细胞功能的因子知之甚少。DiGruccio及其同事产生了一种三重转基因报告小鼠，能够从相同的胰岛中进行α，β和δ细胞的FACS纯化。对三种胰岛细胞类型中的每一种进行综合转录组。在小鼠和人胰岛中进行静态和灌流试验，以测量δ细胞的SST分泌。通过RNA测序、荧光原位杂交（FISH）和qPCR分析，他们发现Ghsr基因在δ细胞中大量且选择性地表达。用生长素释放肽刺激小鼠和人胰岛产生葡萄糖刺激的SST分泌的稳健增加，以及完整小鼠胰岛中δ细胞中钙应答的刺激。Des-Acyl-ghrelin不激活GHSR-1a，不增强SST分泌或阻断ghrelin诱导的SST释放。此外，作者表明ghrelin以SST依赖性方式抑制β细胞的GSIS。
Ghrelin has emerged as an important player in the regulation of glucose homeostasis. During caloric restriction, the presence of acyl ghrelin (the active isoform) is necessary for the defense against hypoglycemia and survival [1]. In fasted humans, ghrelin administration enhances growth hormone (GH) secretion, suppresses insulin release and promotes insulin resistance to maintain normoglycemia [2]. The exact mechanism for the insulinostatic effect of ghrelin is not known. Ghrelin is secreted primarily by gastric endocrine cells, although a novel endocrine cell type (ɛ cells) in the pancreatic islet [3] also produces ghrelin raising the possibility of intra-islet regulation. Ghrelin has been shown to activate its receptor, the GH secretagogue receptor (GHSR) 1a, on β cells to inhibit glucose-stimulated insulin secretion (GSIS) through a Gα i2 signaling pathway [4] and acts directly on α cells to stimulate glucagon secretion by elevating intracellular calcium and promoting ERK phosphorylation [5]. Another major inhibitor of insulin secretion from β cells is somatostatin (SST) through the SST receptor subtype-5 (SSTR5). Park and colleagues reported collaborative actions between ghrelin and SST via their receptors in INS-1 β cells to modulate GSIS during low-and high-energy balance states [6]. The close proximity of islet cells makes it difficult to distinguish between direct and indirect effects of hormones on β cells. However, the recent advances in molecular genetic techniques and next-generation sequencing allows for unbiased evaluation of gene expression in individual cells and provides a unique opportunity to intercept cross talk between pancreatic islet cells. In this issue of Molecular Metabolism, DiBruccio et al.[7] report a novel insulinostatic mechanism of ghrelin by acting directly on δ cells to promote SST release.Little is known about the factors that regulate δ cell function despite these being the third most prevalent islet cell type. DiGruccio and colleagues generated a triple transgenic reporter mouse that enabled FACS purification of α, β and δ cells from the same islets. Comprehensive transcriptomes for each of the three islet cell types was performed. Static and perifusion assays were performed in both mouse and human islets to measure SST secretion from δ cells. Using RNA sequencing, fluorescent in situ hybridization (FISH), and qPCR analyses, they found that the Ghsr gene was abundantly and selectively expressed in δ cells. Stimulation of mouse and human islets with ghrelin produced a robust increase in glucose-stimulated SST secretion, and stimulation of calcium responses in δ cells in intact mouse islets. Des-Acyl-ghrelin, which does not activate the GHSR-1a, did not potentiate SST secretion or block ghrelin-induced SST release. Furthermore, the authors showed that ghrelin inhibited GSIS from β cells in a SST-dependent manner.