We have identified CX3CL1 as a novel adipose tissue chemokine in humans. First, adipose CX3CL1 is increased in obesity as well as in evoked adipose inflammation. Second CX3CL1, which is secreted by adipocytes and adipose SVF, promotes monocyte adhesion to human adipocytes. Third, the association of genetic variation in CX3CR1 with multiple metabolic traits and the finding of higher levels of CX3CL1 in type 2 diabetes provide support for clinical relevance. Thus, CX3CL1 may modulate recruitment of leukocytes in clinical syndromes of adipose inflammation and represent a novel therapeutic target for obesity and type 2 diabetes.
Several inflammatory signaling pathways have been implicated in adipose dysfunction and insulin resistance. In particular, adipose recruitment and activation of macrophages and T-cells play a proximal role in obesity and insulin resistance (2
). However, the specific signals that initiate recruitment of leukocytes to adipose and their activation are unclear, particularly in humans.
We discovered CX3CL1 as a novel adipochemokine induced in human adipose using experimental endotoxemia. Although an acute model, endotoxemia-induced metabolic perturbations (17
) are of specific relevance to chronic changes in diet-induced obesity, insulin resistance, and metabolic syndrome (16
). For example, endotoxemia induces insulin resistance in humans (17
) with adipose inflammation preceding loss of insulin sensitivity (17
). Further, ablation of Toll-like receptor-4 (TLR4), the receptor for endotoxin, in high-fat–diet fed mice attenuates obesity and improves metabolic traits (36
). Recent work demonstrates that certain dietary and adipocyte fatty acids are endogenous TLR4 ligands (36
) and high-fat diets increase plasma LPS and mononuclear cell TLR signaling (39
Inflammatory induction of CX3CL1 in adipose, therefore, raises the possibility of its involvement in the pathogenesis of insulin resistance and type 2 diabetes. Indeed, emerging data implicates CX3CL1 as a unique chemokine in human disease. The soluble form of CX3CL1, cleaved from the membrane by the enzyme ADAM17 or TACE (TNF-α converting enzyme), may be involved in chemotaxis, while the membrane-anchored form promotes adhesion and retention of leukocytes (40
). CX3CL1 modulates monocyte and T-cell recruitment and adherence to endothelium in several chronic inflammatory diseases including atherosclerosis in both rodents (15
) and humans (30
). Experimental studies also suggest that therapeutic blockade of CX3CL1-CX3CR1 may produce fewer side effects than other chemokines because CX3CL1-CX3CR1 play a limited role in homeostasis or acute inflammation (43
Whether CX3CL1-CX3CR1 modulates inflammatory monocyte recruitment to adipose is unknown. Recent work, however, is suggestive; adipose tissue macrophages in obese adipose express high levels of CX3CR1 (45
). We demonstrate that obese human adipose secreted greater amounts of CX3CL1 than lean adipose. Compared with subcutaneous fat, visceral adipose, known to have greater inflammatory leukocyte infiltration (46
), had higher CX3CL1 levels. Consistent with literature demonstrating the endothelium as a source of CX3CL1 (12
), the SVF of adipose secreted CX3CL1. The adipocyte fraction, however, also expressed CX3CL1 with marked induction by adipocytokines (TNF-α and IFN-γ), which are upregulated and implicated in obesity. Given the fundamental role of PPAR-γ in adipocyte differentiation and healthy function, suppression of this phenomenon by a PPAR-γ agonist is consistent with a role of CX3CL1 in early adipose inflammation and adipocyte dysregulation in obesity and insulin resistance. Thus, both adipocytes and SVFs may secrete CX3CL1 and modulate leukocyte recruitment to adipose in obesity.
Like others (34
), we found that CX3CR1 is highly expressed on primary human monocytes and THP-1 monocytes. Using blocking antibodies, we found that THP-1 monocyte adherence to human adipocytes is CX3CL1-CX3CR1–dependent. Several groups recently showed independent and additive effects of CX3CL1-CX3CR1 and CCR2 in atherosclerosis (12
). Remarkably, our preliminary data also show additive effects of CX3CR1 and CCR2 pathways in monocyte-adipocyte interactions raising the possibility that these chemokines may have independent, nonredundant actions in leukocyte recruitment to adipose in obesity. Whether this is true in the pathogenesis of insulin resistance and type 2 diabetes in vivo remains to be established.
In humans, variation in CX3CR1
has been related to monocyte chemotactic function (30
) and atherosclerotic CVD (48
). Recently, Sirois-Gagnon et al. found the association of SNPs in CX3CR1
with obesity. We replicated and extended these findings by showing the association of these SNPs with multiple metabolic traits including metabolic syndrome and type 2 diabetes. Finally, our case-control study found higher CX3CL1 levels in type 2 diabetic subjects compared with control subjects. These data extend our experimental findings by suggesting potential associations of CX3CL1-CX3CR1 with clinically relevant metabolic traits and disease.
CX3CL1-CX3CR1 is a novel adipochemokine system in humans. Its expression in obese adipose, inflammatory upregulation in adipose and adipocytes, modulation of monocyte-adipocyte interactions, and association with human disease traits suggest a role in clinical syndromes of adipose inflammation and its potential as a novel therapeutic target in obesity and type 2 diabetes. Future studies in rodents with gene deficiency and humans using pharmacological modulation are required to define the causal role of CX3CL1-CX3CR1 in adipose inflammation, insulin resistance, and type 2 diabetes.