Autocrine and Paracrine Communication within Adipose Tissue
Regulation of adipocyte function, adipogenesis and plasticity through local signaling between cell types in adipose tissue via metabolites and peptides with focus on GPCR sensing.
Classically, adipocytes take up, store, and burn or excrete metabolites as fuel in exchange with other organs and they produce signaling peptides, adipokines and BATokines, which generally are considered to function in organ crosstalk.
This Flagship project portfolio deals with a novel concept where key metabolites and peptides instead function as autocrine and paracrine extracellular signals between the different cell types – including subtypes of adipocytes – within the adipose tissue and how these signals are sensed by specific GPCRs to be integrated with nervous and hormonal signals to control function of mature adipocytes as well as adipogenesis and remodeling under physiological and pathophysiological states.
This challenging project portfolio requires and exploits the development at CBMR of novel cutting-edge technologies within single cell transcriptomics and proteomics, spatial transcriptomics, microdialysis, metabolomics, 3D co-culturing, multiplex in situ hybridization, adipocyte sub-type specific gene editing and use of unique, in-house developed pharmacological GPCR tool compounds.
At CBMR, the Flagship project portfolio is centered around the adipose-focused groups of Camilla Schéele (BATokines), Zach Gerhart-Hines (mitochondrial bioenergetics) and Brice Emanuelli as well as the GPCR-focused group of Thue W. Schwartz.
Importantly, the projects will also thrive upon metabolite generating enzymological expertise of the group of Kei Sakamoto, single-cell analysis expertise of the group of Tune H. Pers, proteomics expertise of the group of Atul Deshmukh, and computational chemistry expertise of the Computational Chemistry Unit (Thomas Frimurer), which generates pharmacological tool compounds. The projects will obviously also exploit our other enabling platforms including the Metabolomics Platform (Thomas Moritz) and the Phenomics Platform (Niels Grarup) and will also include collaborations with other genetically focused groups at CBMR.
Among close collaborators in Denmark will be Susanne Mandrup’s Challenge Grant ‘Center for Adipocyte Signaling’ (ADIPOSIGN) of which Zach Gerhart-Hines is a partner. Internationally, major collaborators include Christian Wolfrum at ETH Zürich and Jens Brüning, Cologne.
In adipose tissue, the non-adipocyte, vascular-stromal cell populations can account for up to more than 50% of the cells, dependent on the depot and the physiological or pathophysiological state. Importantly, single cell analysis has revealed surprising heterogeneity even among mature adipocytes, identifying novel subpopulations that apparently function differently and at different times within a given depot (Scheele & Wolfrum, Endocr.Rev. 2020).
This Flagship project portfolio focuses on autocrine and paracrine communication between adipocytes and stromal cells in adipose tissue – importantly, between different subtypes of adipocytes – and how this communication controls adipogenesis, adipocyte function as well as tissue plasticity and remodeling.
Groups at CBMR are at the forefront of characterizing cell types and sub-types in different adipose depots by mass spectrometry (Deshmukh et al. 2019) and by single cell transcriptomics and collaborate closely with other, international groups on this (Sun et al. 2020; Timshel et al in prep.). However, characterization of the elusive functional interplay between different, neighboring cell types within the adipose microenvironment requires employment and development of novel techniques to study gene expression and function at the single cell histological level.
Thus, at CBMR we are developing, for example, novel, unbiased spatial transcriptomics and multiplex RNA scope, in situ hybridization methods to understand which cell type and subtype express specific signaling peptides or express the enzymatic and transporter machinery generating signaling metabolites and which cells express the cognate receptors they act on. This is being integrated with, for example, refined metabolomics/microdialysis methods and ex vivo 3D co-culture systems of different cell types. In respect of intervention methods, we are employing cutting edge techniques for time and cell-(sub)type specific gene KO and overexpression for both ex vivo and in vivo studies. Importantly, we are developing unique, proprietary pharmacological tool compounds to, e.g. differentiate between effects of a signaling metabolite through its GPCR sensor and effects mediated as a classical metabolite (Trauelsen et al. 2020).
The portfolio includes Flagship projects on classical and novel peptide/protein messengers, as well as projects that focus on signaling metabolites and their novel function in intra-adipose communication through activation of cell surface GPCR sensors (Husted et al. 2017) and how these local signals are integrated with each other and with nervous and external hormonal signals. This currently includes, but is not restricted to the following projects:
- How brown and white adipocytes interact with the newly identified, co-differentiated cell types during differentiation and in tissue plasticity (Camilla Schéele)
- How BAT acts as a metabolic regulator through BAT-Brain crosstalk (Camilla Schéele).
- Control of plasticity in brown and brite thermogenic fat through autocrine/paracrine crosstalk between adipocytes and vascular stromal cells by CXCL12 and its receptor CXCR4 (Brice Emanuelli)
- How lipid, metabolite, and hormonal cues shape the adipose GPCRome (Zach Gerhart-Hines) (Johansen et al. 2020).
- Finetuning of adipocyte function through autocrine/paracrine signaling between adipocyte subtypes and stromal cells by fuel and stress-signaling metabolites and their GPCR sensors (Zach Gerhart-Hines and Thue W. Schwartz)
Brown Adipose Crosstalk in Tissue Plasticity and Human Metabolism. Scheele, Camilla; Wolfrum, Christian. In: Endocrine Reviews, Vol. 41, No. 1, 2020, p. 53-65.
GPCR-Mediated Signaling of Metabolites. Husted AS et al. Cell Metabol (2017) 25: 777-796.
Proteomics-Based Comparative Mapping of the Secretomes of Human Brown and White Adipocytes Reveals EPDR1 as a Novel Batokine. Deshmukh AS et al. Cell Metab. (2019) 30: 963-975.
Single-nucleus RNA-Seq reveals a new type of adipocyte which regulates thermogenesis
Sun W, Dong H, Balzac M, Slyper M, Drokhlyansky E, Colleluori G, Giordano A, Kovanicova Z, Stefanicka P, Balazova L, Ding L, Husted AS, Rudolfsky G, Ukropec J, Cinti S, Schwartz TW. Regev A and Wolfrum C. Nature (2020) (in press).
Single-cell trajectory analysis of differentiating human adipocytes reveals common metabolic and structural cell fates across brown and white fat depots
Timshel PN, Folkertsma P, Palani N, Grønning A, Larsen TJ, Peijs L, Jensen VH, Sun W, Jespersen NZ, Barrès R, Wolfrum C, Pers TH, Nielsen S and Scheele C. (In preparation).
Lipolysis-driven Transcriptional Control of the Constitutively Active Receptor GPR3 Drives Adipose Thermogenesis
Johansen O et al. et Gerhart-Hines Z. (In review).
Succinate regulates expression of cell-specific immunological genes in M2 macrophages through SUCNR1/GPR91
Trauelsen M et al. et Schwartz TW. (In revision).