Modulation of Gr1(low) monocyte subset impacts insulin sensitivity and weight gain upon high-fat diet in female mice

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 Gr1(low) monocyte subset upon high-fat diet (HFD). METHODS: We used transgenic female mouse models allowing the modulation of circulating Gr1(low) 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 Gr1(low) monocyte expansion, and was associated with a specific upregulation of CD11c on that subset. Using mice models with altered Gr1(low) monocyte number, we found a striking correlation between Gr1(low) monocytes, bodyweight (BW) and insulin resistance (RT) status. Indeed, CX3CR1(−/−) female mice, with reduced Gr1(low) 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 Gr1(low) monocytes, higher insulin sensitivity upon HFD and an anti-inflammatory profile of the AT. Finally, increasing Gr1(low) monocytes in Gr1(low)-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 Gr1(low) monocyte subset and weight gain and RT. Hence, this specific Gr1(low) monocyte subset could be used as a target for acting on AT inflammation and RT.