Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin

• Published in: Cell metabolism Vol. 33; no. 9; pp. 1869 - 1882.e6
• Main Authors: Bäckdahl, Jesper, Franzén, Lovisa, Massier, Lucas, Li, Qian, Jalkanen, Jutta, Gao, Hui, Andersson, Alma, Bhalla, Nayanika, Thorell, Anders, Rydén, Mikael, Ståhl, Patrik L., Mejhert, Niklas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.09.2021
• Subjects: Adipocytes; Adipose Tissue; Adipose Tissue, White; Humans; Insulin - pharmacology; Insulin Resistance; insulin sensitivity; obesity; single-cell RNA sequencing; spatial transcriptomics; type 2 diabetes; single-cell RNA sequencing; insulin sensitivity; type 2 diabetes; spatial transcriptomics; obesity
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2021.07.018

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 AdipoLEP, AdipoPLIN, and AdipoSAA. 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 AdipoPLIN 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. [Display omitted] •Spatial mapping of human subcutaneous white adipose tissue detects 18 cell types•Neighborhood analyses identify cell classes with distinct clustering propensities•We report three fat cell types with specific localization and mRNA/protein markers•Only one of the three adipocyte subtypes responds to insulin stimulation in vivo Tissue microarchitecture and cell composition are major determinants of organ function. Here, Bäckdahl et al. apply spatial transcriptomics to human white adipose tissue. This reveals that the tissue is more spatially defined than expected and identifies three distinct mature adipocyte subtypes with qualitatively different sensitivities to insulin stimulation in vivo.