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

Abstract

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). 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. 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. 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.