Corrupted adipose tissue endogenous myelopoiesis initiates diet-induced metabolic disease.

Elodie Luche,Beatrice Cousin,Aurélie Waget,Vincent Cuminetti,Emmanuelle Arnaud,Remy Burcelin,Patrick Laharrague,Louis Casteilla,Quentin Sastourné-Arrey,Celine Pomié,Virginie Robert,Audrey Varin,Elodie Labit

doi:10.7554/elife.23194

Abstract

Activation and increased numbers of inflammatory macrophages, in adipose tissue (AT) are deleterious in metabolic diseases. Up to now, AT macrophages (ATM) accumulation was considered to be due to blood infiltration or local proliferation, although the presence of resident hematopoietic stem/progenitor cells (Lin-/Sca+/c-Kit+; LSK phenotype) in the AT (AT-LSK) has been reported. By using transplantation of sorted AT-LSK and gain and loss of function studies we show that some of the inflammatory ATM inducing metabolic disease, originate from resident AT-LSK. Transplantation of AT-LSK sorted from high fat diet-fed (HFD) mice is sufficient to induce ATM accumulation, and to transfer metabolic disease in control mice. Conversely, the transplantation of control AT-LSK improves both AT-inflammation and glucose homeostasis in HFD mice. Our results clearly demonstrate that resident AT-LSK are one of the key point of metabolic disease, and could thus constitute a new promising therapeutic target to fight against metabolic disease.

Highlights

Over the last two decades a critical role of adipose tissue macrophages (ATM) in the initiation of the metabolic inflammation, commonly found in highly prevalent chronic diseases such as obesity, has been largely documented (Chawla et al, 2011)
To investigate whether some of the inflammatory macrophages in the AT could originate from ATLSK during metabolic disease, chimeric mice were generated by using standard repopulation assays as previously described (Poglio et al, 2012) by injecting 2.103 sorted Subcutaneous inguinal adipose tissue (scAT)-LinÀ/Sca-1+/ c-Kit+ (LSK) mixed with 2.105 congenic bone marrow (BM) cells isolated from congenic CD45 variants
ScAT-glucose uptake. (g) Quantification of ATM identified as F4/80+/MHCII+ in the scAT. (h) Expression of genes encoding for inflammatory cytokines analyzed by qRT-PCR in the scAT and expressed as a percent of control values obtained in normal chow (NC) mice. (i–n) Flow cytometry was performed on stroma-vascular fraction (SVF) and BM cells from NC and high-fat diet (HFD) mice to identify CD45.1+ populations

Summary

Introduction

Over the last two decades a critical role of adipose tissue macrophages (ATM) in the initiation of the metabolic inflammation, commonly found in highly prevalent chronic diseases such as obesity, has been largely documented (Chawla et al, 2011). Most of the literature supports the idea that ATM cause disease, accumulating evidences recently show that these ATM have beneficial effects in obesity. Different molecular tools such as lipid storage (Aouadi et al, 2014), autophagy (Fitzgibbons and Czech, 2016), or program of lysosomal metabolism (Xu et al, 2013) are used by the ATM to buffer and process excessive amounts of lipids and maintain adipose tissue (AT) homeostasis, in the context of metabolic disease. Our results provide a new mechanism for the increase in pro-inflammatory ATM in metabolic diseases and point out AT-LSK as novel regulator of these pathologies

Results

Discussion

Materials and methods