Piñeros Annie R, Gao Hongyu, Wu Wenting, Liu Yunlong, Tersey Sarah A, Mirmira Raghavendra G
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Metabolites. 2020 Dec 18;10(12):513. doi: 10.3390/metabo10120513.
Obesity is closely associated with adipose tissue inflammation and insulin resistance. Dysglycemia and type 2 diabetes results when islet β cells fail to maintain appropriate insulin secretion in the face of insulin resistance. To clarify the early transcriptional events leading to β-cell failure in the setting of obesity, we fed male C57BL/6J mice an obesogenic, high-fat diet (60% kcal from fat) or a control diet (10% kcal from fat) for one week, and islets from these mice (from four high-fat- and three control-fed mice) were subjected to single-cell RNA sequencing (sc-RNAseq) analysis. Islet endocrine cell types (α cells, β cells, δ cells, PP cells) and other resident cell types (macrophages, T cells) were annotated by transcript profiles and visualized using Uniform Manifold Approximation and Projection for Dimension Reduction (UMAP) plots. UMAP analysis revealed distinct cell clusters (11 for β cells, 5 for α cells, 3 for δ cells, PP cells, ductal cells, endothelial cells), emphasizing the heterogeneity of cell populations in the islet. Collectively, the clusters containing the majority of β cells showed the fewest gene expression changes, whereas clusters harboring the minority of β cells showed the most changes. We identified that distinct β-cell clusters downregulate genes associated with the endoplasmic reticulum stress response and upregulate genes associated with insulin secretion, whereas others upregulate genes that impair insulin secretion, cell proliferation, and cell survival. Moreover, all β-cell clusters negatively regulate genes associated with immune response activation. Glucagon-producing α cells exhibited patterns similar to β cells but, again, in clusters containing the minority of α cells. Our data indicate that an early transcriptional response in islets to an obesogenic diet reflects an attempt by distinct populations of β cells to augment or impair cellular function and/or reduce inflammatory responses as possible harbingers of ensuing insulin resistance.
肥胖与脂肪组织炎症和胰岛素抵抗密切相关。当胰岛β细胞在面对胰岛素抵抗时无法维持适当的胰岛素分泌，就会导致血糖异常和2型糖尿病。为了阐明在肥胖情况下导致β细胞功能衰竭的早期转录事件，我们给雄性C57BL/6J小鼠喂食致肥胖的高脂肪饮食（脂肪提供60%的千卡热量）或对照饮食（脂肪提供10%的千卡热量）一周，然后对这些小鼠（来自4只喂食高脂肪饮食和3只喂食对照饮食的小鼠）的胰岛进行单细胞RNA测序（sc-RNAseq）分析。胰岛内分泌细胞类型（α细胞、β细胞、δ细胞、PP细胞）和其他驻留细胞类型（巨噬细胞、T细胞）通过转录谱进行注释，并使用均匀流形近似和投影降维（UMAP）图进行可视化。UMAP分析揭示了不同的细胞簇（β细胞有11个，α细胞有5个，δ细胞、PP细胞、导管细胞、内皮细胞各有3个），强调了胰岛中细胞群体的异质性。总体而言，包含大多数β细胞的簇显示出最少的基因表达变化，而包含少数β细胞的簇显示出最多的变化。我们发现，不同的β细胞簇下调与内质网应激反应相关的基因，上调与胰岛素分泌相关的基因，而其他簇则上调损害胰岛素分泌、细胞增殖和细胞存活的基因。此外，所有β细胞簇均对与免疫反应激活相关的基因起负调控作用。产生胰高血糖素的α细胞表现出与β细胞相似的模式，但同样是在包含少数α细胞的簇中。我们的数据表明，胰岛对致肥胖饮食的早期转录反应反映了不同群体的β细胞试图增强或损害细胞功能和/或减少炎症反应，这些可能是随后胰岛素抵抗的先兆。
