Single Cell Analysis Reveals Immune Cell-Adipocyte Crosstalk Regulating the Transcription of Thermogenic Adipocytes

Abstract

Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor a in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. Single Nuclei Adipocyte RNA-sequencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Ra deletion.Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function.3

Induction of Adipose Tissue Browning as a Strategy to Combat Obesity

“…Several lines of evidence suggest that WAT browning also depends on proper eosinophil-derived cytokines activity (namely interleukin (IL) 4/IL-13 signaling), which is necessary for the alternative activation of anti-inflammatory M2 macrophages [ 24 ]. The thermogenic challenge is also associated with the expansion of adaptive immune cell populations and upregulation of interleukin 10 production, which antagonizes adrenergic-mediated thermogenesis, providing a mechanism whereby the immune system helps control the consumption of energy reserves [ 25 ].…”

The Impact of Single-Cell Genomics on Adipose Tissue Research

“…Having already proven that IL10 depletion promotes thermogenesis and confers diet-induced obesity resistance in mice [ 30 ], they sought to further dissect the role that immune cells play in this process. Upon thermogenic challenge, they witnessed an expansion in adaptive immune cell populations and upregulation of IL10 production in these subtypes, which antagonized thermogenesis, as hypothesized [ 31 ]. These studies illustrate the functional specialization of thermogenic adipose-resident immune cells and their dedicated role in thermal homeostasis.…”

“…As aforementioned, the direct application of scRNA-seq to mature, lipid-containing adipocytes has been challenging due to the large size and high buoyancy of white adipocytes. To overcome this, researchers have taken three different approaches: (1) Harvesting single mature brown adipocytes by precise pipetting, followed by the generation of an RNA-seq library [ 33 ]; (2) limiting their analysis to relatively small thermogenic adipocytes and then running scRNA-seq [ 34 ]; and (3) isolating nuclei and running single nuclei RNA-sequencing [ 31 ]. We will review each of these three approaches below.…”

The Heating Microenvironment: Intercellular Cross Talk Within Thermogenic Adipose Tissue

“…New evidence has since emerged demonstrating that gd T cell-derived IL-17F signals directly to adipocytes expressing the IL-17 receptor C (IL-17RC), eliciting sympathetic innervation of adipose tissue in a TGFb1-dependent manner (35). Building upon previous work showing that bone marrow-derived IL-10 repressed transcription of thermogenic genes in adipocytes (36), Tontonoz and colleagues have since demonstrated that IL-10 produced by T and B lymphocytes impaired the activation of IL10Ra-expressing beige precursors, modulating the induction of thermogenesis and systemic energy balance (10).…”