Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin

Jesper Bäckdahl,Lovisa Franzén,Lucas Massier,Qian Li,Jutta Jalkanen,Hui Gao,Alma Andersson,Nayanika Bhalla,Anders Thorell,Mikael Rydén,Patrik L Ståhl,Niklas Mejhert

doi:10.1016/j.cmet.2021.07.018

Jesper Bäckdahl, Lovisa Franzén + Show 10 more

Open Access

https://doi.org/10.1016/j.cmet.2021.07.018

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Abstract

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 invivo 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.

Highlights

White adipose tissue (WAT) plays important roles in energy homeostasis by storing and releasing lipids and by secreting factors regulating caloric intake
Article human subcutaneous abdominal WAT by performing spatial transcriptomics using the Visium platform (10x Genomics) and combining it with single-cell RNA sequencing data as well as neighborhood and image analyses. Mining of this resource together with functional in vivo studies performed in humans allowed us to identify three fat cell populations that display distinct spatial localizations and differential responses to insulin, suggesting that adipocyte heterogeneity is a determinant of WAT insulin sensitivity
We provide a spatial map of human WAT organization and demonstrate that the tissue is composed of multiple cell types that are arranged in specific areas

Summary

Introduction

White adipose tissue (WAT) plays important roles in energy homeostasis by storing and releasing lipids and by secreting factors regulating caloric intake. To obtain insights into the cellular complexity of WAT, single-cell analyses have recently been applied to both murine and human adipose depots (Acosta et al, 2017; Gu et al, 2019; Sun et al, 2020; Vijay et al, 2020; Weinstock et al, 2019). These efforts cannot interrogate the spatial relationship between cells. The few groups that have included fat cells have performed analyses based on isolated nuclei where no information on fat cell morphology or tissue localization was available (Sarvari et al, 2021; Sun et al, 2020)

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