Adipose tissue macrophages (ATMs) accumulation through CCR2 and its ligand MCP-1 is considered pivotal in the development of insulin resistance. Recently, we found that CX3C chemokine, fractalkine (CX3cl1) mRNA expression was persistently downregulated in epididymal white adipose tissue (eWAT) of HF diet (HFD)-induced obese (DIO) mice, as compared to lean controls. Furthermore, we demonstrated that loss of fractalkine receptor, CX3CR1, exacerbated HFD-induced insulin resistance and glucose intolerance. Here, we show that fractalkine-CX3CR1 signaling plays a crucial role in the inflammatory response to HF feeding by regulating macrophage M1/M2 status. To determine the effect of fractalkine-CX3CR1 signaling on ATM subsets, we performed flow cytometry analysis to quantify M1/M2 ATMs in eWAT of CX3CR1-/- (KO) and WT mice. Immunofluorescence study of eWAT in DIO mice revealed that CX3CR1 was predominantly expressed by F4/80+ macrophages in crown-like structures (CLS). On an HFD, KO mice had increased macrophage infiltration and formation of CLS in eWAT compared with those of WT mice, despite that weight and adipocyte size were similar. KO mice had 40% or 39% more CD11c+CD206- (M1) ATMs on normal chow (NC) or HFD, and 17% or 49% fewer CD11c-CD206+ (M2) ATMs on NC or HFD, respectively, than WT mice, resulting in predominance of the M1 over M2 ATM population. Furthermore, the predominance of the Ly6Chi over the Ly6C- monocyte population was observed in the peripheral blood and bone marrow (BM) of KO mice on NC or HFD. Importantly, HFD-induced adipose inflammation and hyperinsulinemia were aggravated in chimeric mice lacking CX3CR1 only in myeloid cells (BM transplant of KO to WT) as compared to control mice (BM transplant of WT to WT). Thus, loss of fractalkine-CX3CR1 signaling causes M1 dominant phenotypic shift in ATMs, which contributes to exacerbation of obesity-induced adipose tissue inflammation and insulin resistance.
M. Nagashimada: None. Y. Ni: None. T. Ota: None.