Partial depletion of CD206-positive M2-like macrophages induces proliferation of beige progenitors and enhances browning after cold stimulation

Yoshiko Igarashi,Isao Usui,Seiji Yamamoto,Shiho Fujisaka,Masakiyo Sasahara,Takahide Kuwano,Naotoshi Shibahara,Xu Jiuxiang,Keiichi Koizumi,Johji Imura,Tomonobu Kado,Allah Nawaz,Muhammad Bilal,Kazuyuki Tobe,Akiko Inujima

doi:10.1038/s41598-018-32803-6

Yoshiko Igarashi, Isao Usui + Show 13 more

Open Access

https://doi.org/10.1038/s41598-018-32803-6

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Journal: Scientific Reports	Publication Date: Oct 1, 2018
Citations: 24	License type: open-access

Affiliation: University of Toyama, Dokkyo Medical University

Abstract

Beige adipocytes are an inducible form of thermogenic adipocytes that become interspersed within white adipose tissue (WAT) depots in response to cold exposure. Previous studies have shown that type 2 cytokines and M2 macrophages induce cold-induced browning in inguinal WAT (ingWAT) by producing catecholamines. Exactly how the conditional and partial depletion of CD206+ M2-like macrophages regulates the cold-induced browning of ingWAT, however, remains unknown. We examined the role of CD206+ M2-like macrophages in the cold-induced browning of WAT using genetically engineered CD206DTR mice, in which CD206+ M2-like macrophages were conditionally depleted. The partial depletion of CD206+ M2-like enhanced UCP1 expression in ingWAT, as shown by immunostaining, and also upregulated the expression of Ucp1 and other browning-related marker genes in ingWAT after cold exposure. A flow cytometry analysis showed that the partial depletion of CD206+ M2-like macrophages caused an increase in the number of beige progenitors in ingWAT in response to cold. Thus, we concluded that CD206+ M2-like macrophages inhibit the proliferation of beige progenitors and that the partial depletion of CD206+ M2-like macrophages releases this inhibition, thereby enhancing browning and insulin sensitivity.

Highlights

2 cytokines and M2 macrophages induce cold-induced browning in inguinal White adipose tissue (WAT) by producing catecholamines
We found that the expression of M1-like macrophage marker genes including Tnfa, Il1b, Mcp[1] and Cd11c were upregulated in the inguinal WAT (ingWAT) of Diphtheria toxin (DT)-treated Tg mice compared with their littermate controls at room temperature (RT) and at the cold temperature
A flow cytometry analysis further showed that the percentage of M2-like macrophages (F4/80+CD206+) in the CD45+ fraction of ingWAT stromal vascular fraction (SVF) was significantly decreased in DT-injected Tg mice compared with DT-administered WT mice maintained at both cold temperatures and RT (Fig. 1F and Fig. S4E)

Summary

Introduction

2 cytokines and M2 macrophages induce cold-induced browning in inguinal WAT (ingWAT) by producing catecholamines. Previous reports have shown that M2-like macrophages play a key role in the induction of browning in ingWAT via the activation of type 2 cytokine production during cold exposure[17,18,19,20] and other stimuli that activate the sympathetic nervous system[10]. Whether these mechanisms are catecholamine-dependent[17,18,21] or catecholamine-independent[22,23] remains a matter of debate. We examined the effect of the partial depletion of CD206+ M2-like macrophages on the browning of ingWAT in response to cold using previously generated genetically engineered CD206DTR transgenic mice[12]

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Conclusion