CXCL5 secreted from macrophages during cold exposure mediates white adipose tissue browning

Dabin Lee,Dong Wook Kim,Sanghyuk Yoon,A-Reum Nam,Kang-Hoon Lee,Ki-Hoan Nam,Sang-Mi Cho,Yeodae Yoon,Je-Yoel Cho

doi:10.1016/j.jlr.2021.100117

Abstract

Adipose tissue affects metabolic-related diseases because it consists of various cell types involved in fat metabolism and adipokine release. CXC ligand 5 (CXCL5) is a member of the CXC chemokine family and is highly expressed by macrophages in white adipose tissue (WAT). In this study, we generated and investigated the function of CXCL5 in knockout (KO) mice using CRISPR/Cas9. The male KO mice did not show significant phenotype differences in normal conditions. However, proteomic analysis revealed that many proteins involved in fatty acid beta-oxidation and mitochondrial localization were enriched in the inguinal WAT (iWAT) of Cxcl5 KO mice. Cxcl5 KO mice also showed decreased protein and transcript expression of genes associated with thermogenesis, including uncoupling protein 1 (UCP1), a well-known thermogenic gene, and increased expression of genes associated with inflammation. The increase in UCP1 expression in cold conditions was significantly retarded in Cxcl5 KO mice. Finally, we found that CXCL5 treatment increased the expression of transcription factors that mediate Ucp1 expression and Ucp1 itself. Collectively, our data show that Ucp1 expression is induced in adipocytes by CXCL5, which is secreted upon β-adrenergic stimulation by cold stimulation in M1 macrophages. Our data indicate that CXCL5 plays a crucial role in regulating energy metabolism, particularly upon cold exposure. These results strongly suggest that targeting CXCL5 could be a potential therapeutic strategy for people suffering from disorders affecting energy metabolism.

Highlights

CXC ligand 5 (CXCL5) is a cold-inducible chemokine in inguinal white adipose tissue (WAT) (iWAT)
To determine cold-responsive chemokines in the iWAT of mice, we mainly focused on the ligand chemokines of CXCR2 such as CXCL1, CXCL2, CXCL5, and CXCL12 (Fig. 1A)
Both 1-day and 7-day cold exposures significantly increased CXCL5 chemokine protein expression in iWAT when compared with the control (Fig. 1B)

Summary

Introduction

We used proteomic analysis with iWAT in both wild-type (WT) and Cxcl5 knockout (KO) mice to demonstrate the function of CXCL5 in adipose tissue and its browning after cold exposure. Both 1-day and 7-day cold exposures significantly increased CXCL5 chemokine protein expression in iWAT when compared with the control (Fig. 1B).

Results

Conclusion