The contribution of cellular heterogeneity and architecture to white adipose tissue (WAT) function is poorly understood. Herein, we combined spatially resolved transcriptional profiling with single-cell RNA sequencing and image analyses to map human WAT composition and structure. This identified 18 cell classes with unique propensities to form spatially organized homo- and heterotypic clusters. Of these, three constituted mature adipocytes that were similar in size, but distinct in their spatial arrangements and transcriptional profiles. Based on marker genes, we termed these Adipo^LEP, Adipo^PLIN, and Adipo^SAA. We confirmed, in independent datasets, that their respective gene profiles associated differently with both adipocyte and whole-body insulin sensitivity. Corroborating our observations, insulin stimulation in vivo by hyperinsulinemic-euglycemic clamp showed that only Adipo^PLIN displayed a transcriptional response to insulin. Altogether, by mining this multimodal resource we identify that human WAT is composed of three classes of mature adipocytes, only one of which is insulin responsive.

细胞异质性和结构对白色脂肪组织 (WAT) 功能的贡献知之甚少。在这里，我们将空间分辨的转录分析与单细胞 RNA 测序和图像分析相结合，以绘制人类 WAT 的组成和结构。这确定了 18 个具有形成空间组织同型和异型簇的独特倾向的细胞类别。其中，三个构成成熟的脂肪细胞，大小相似，但空间排列和转录谱不同。基于标记基因，我们将这些 Adipo ^LEP、Adipo ^PLIN和 Adipo ^SAA命名为. 我们在独立的数据集中证实，它们各自的基因谱与脂肪细胞和全身胰岛素敏感性的相关性不同。证实了我们的观察，通过高胰岛素-正常血糖钳在体内刺激胰岛素表明只有 Adipo ^PLIN显示出对胰岛素的转录反应。总之，通过挖掘这种多模式资源，我们发现人类 WAT 由三类成熟的脂肪细胞组成，其中只有一种对胰岛素有反应。