Modulation of Gr1low monocyte subset impacts insulin sensitivity and weight gain upon high-fat diet in female mice

S Béliard,L Bouchareychas,W Le Goff,P Lesnik,V Deswaerte,L Poupel,T Huby,F Saint-Charles

doi:10.1038/ijo.2017.179

Abstract

Background/Objectives:Blood monocytes are expanded during obesity. However, the differential contribution of monocyte subsets in obesity-related metabolic disorders remains unknown. The aim of the study was to define the role of the Gr1low monocyte subset upon high-fat diet (HFD).Methods:We used transgenic female mouse models allowing the modulation of circulating Gr1low monocyte number (decreased number in CX3CR1−/− mice and increased number in CD11c-hBcl2 mice) and studied obesity upon HFD.Results:We reported here that HFD induced monocytosis in mice, preferentially due to Gr1low monocyte expansion, and was associated with a specific upregulation of CD11c on that subset. Using mice models with altered Gr1low monocyte number, we found a striking correlation between Gr1low monocytes, bodyweight (BW) and insulin resistance (RT) status. Indeed, CX3CR1−/− female mice, with reduced Gr1low monocytes upon HFD, showed increased RT and a pro-inflammatory profile of the adipose tissue (AT) despite a lower BW. Conversely, mice expressing the anti-apoptotic gene hBcl2 in CD11c-expressing cells have increased Gr1low monocytes, higher insulin sensitivity upon HFD and an anti-inflammatory profile of the AT. Finally, increasing Gr1low monocytes in Gr1low-defective CX3CR1−/− mice rescued BW loss in these mice.Conclusions:By using transgenic female mice and adoptive transfer experiments, we established the evidence for a correlation between Gr1low monocyte subset and weight gain and RT. Hence, this specific Gr1low monocyte subset could be used as a target for acting on AT inflammation and RT.

Highlights

Obesity and its associated complications such as type 2 diabetes, cardiovascular diseases, cancers and premature mortality has become a worldwide health problem
We observed that Gr1low monocytes expressed higher levels of CD11c compared with Gr1high monocyte subset in mice maintained on a chow diet (358 ± 130 vs 186 ± 71 mean fluorescence intensity, P o 0.001; Figure 1e)
Using transgenic mouse models, which differ in the proportion of circulating Gr1low monocytes under high-fat diet (HFD), we established a strong correlation between the number of circulating Gr1low monocytes and BW gain and insulin sensitivity

Summary

Introduction

Obesity and its associated complications such as type 2 diabetes, cardiovascular diseases, cancers and premature mortality has become a worldwide health problem. Over the last decade, growing evidences have emerged bringing up a close link between obesity and immunity.[1] Obesity is characterized by a chronic low-grade inflammation generating metabolic complications.[2] This low-grade inflammation occurred at a systemic level as well as in different tissues. In adipose tissue (AT), in liver and muscles, obesityinduced inflammation is characterized by an infiltration of proinflammatory macrophages (called M1) secreting pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6.3 These pro-inflammatory cytokines are thought to be responsible for insulin resistance (IR) locally and at a systemic level.[4,5] On the other hand, in lean subjects, alternatively activated macrophages (called M2) are important for maintaining homeostasis in AT.[6]

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