We found that uric acid can increase expression and release of MCP-1 and reduce production of adiponectin in cultured adipocytes. We further showed that an increase in MCP-1 with a reduction in adiponectin occurs in both adipose tissue and serum of the obese, hyperuricemic Pound mice, and that lowering uric acid can attenuate these changes. Obesity is associated with an increase in MCP-1 production (27
) and a decrease in the adiponectin production (19
) in the adipose tissue. These changes contribute substantially to the obesity-related low-grade inflammation and metabolic syndrome, including insulin resistance and hypertension (17
). A dramatic increase in macrophage infiltration with expression of the proinflammatory cytokine TNF-α was observed in visceral adipose tissue in obese mice and is consistent with reported results (42
). Importantly, lowering uric acid caused a reduction in macrophage infiltration and TNF-α expression as well as improved insulin sensitivity and blood pressure. This study may provide a mechanism linking hyperuricemia, obesity, and metabolic syndrome that has been shown previously in clinical studies (4
). The observation that lowering uric acid improved but did not reverse the changes in MCP-1 and adiponectin, inflammation, and insulin resistance in the Pound mouse is consistent with uric acid being a modifying factor—but not the sole causal factor—in driving these changes.
We observed an increase in serum uric acid in the Pound mice and other animal models of obesity in comparison with the corresponding lean controls. This observation is in agreement with published data (38
). Hyperuricemia progressed as animals gained weight, and the level of uric acid correlated with the body weight. As these mice are obese and insulin-resistant because of the mutation in the leptin receptor (39
), hyperuricemia cannot be considered as a causal factor of obesity in this case. However, an increase in uric acid contributed to the low-grade inflammation and metabolic syndrome via its direct effect on the production of MCP-1 and adiponectin in the adipose tissue.
In mouse 3T3-L1 adipocytes and human primary adipocytes, uric acid can induce a direct dose-dependent increase in the production of MCP-1 and a decrease in the production of adiponectin at the level of the mRNA expression and protein release. For mice, cells responded to uric acid beginning at concentrations of 5 mg/dL, which is similar to the levels of uric acid in the obese Pound mice. In the case of human adipocytes, cells responded to 7.5–15 mg/dL uric acid, which encompass the range observed in subjects with asymptomatic hyperuricemia to severe gout (3
The ability of soluble uric acid to induce MCP-1 expression was first demonstrated in rat vascular smooth muscle cells (31
). The effect of uric acid was mediated by MAP kinases ERK1/2 and p38 and nuclear factor-κB in a redox-dependent fashion (31
). In our previous work with 3T3-L1 adipocytes (15
), we showed that uric acid induced ROS production via activation of NADPH oxidase followed by phosphorylation of p38. The urate-induced increase in the MCP-1 expression in adipocytes was downregulated by a superoxide scavenger and a NOX inhibitor. Collectively, these data suggest that uric acid induced MCP-1 production in adipocytes via the redox-dependent signaling initiated by NOX activation. Furukawa et al. (45
) reported that obesity was associated with oxidative stress in adipose tissue, which, in turn, caused an overexpression of a variety of proinflammatory cytokines including MCP-1. We observed an increase in oxidative stress in our mouse model of obesity by measuring MDA in the adipose tissue and serum. This was reduced by allopurinol, suggesting that hyperuricemia induced by obesity is another mechanism triggering oxidative stress followed by induction of the MCP-1 expression and inflammation in the adipose tissue.
The uric acid–induced increase in the MCP-1 production observed in adipocytes was prevented not only by antioxidants but also by activation of PPAR-γ with rosiglitazone. An activation of PPAR-γ is known to block the proinflammatory effects of TNF-α in adipocytes by affecting the proinflammatory branch of the nuclear factor-κB–dependent signaling (48
). XOR in adipocytes is thought to be a crucial upstream regulator of PPAR-γ activity (38
). Treating adipocytes with exogenous uric acid reduced expression of XOR, which could be a cause of downregulated anti-inflammatory activity of PPAR-γ and facilitated redox-dependent MCP-1 production.
The mechanism of downregulation of the adiponectin production in obesity is not completely understood but appears to involve proinflammatory pathways (48
), oxidative stress (45
), and a deficiency in the PPAR-γ activity (48
). The uric acid–induced decrease in adiponectin expression and secretion in our experiments was preventable by the PPAR-γ agonist, rosiglitazone, suggesting an involvement of the same kind of proinflammatory mechanism that was responsible for the induction of MCP-1. On the other hand, antioxidants could not improve adiponectin production affected by uric acid. We can suggest therefore that the deficiency of PPAR-γ but not oxidative stress was a primary trigger of this downregulation.
Because rosiglitazone prevented the uric acid–induced induction of MCP-1 and downregulation of adiponectin, these effects of uric acid might depend on PPAR-γ. XOR-dependent regulation of the adipocyte differentiation via control of PPAR-γ activity is known to be a finely orchestrated mechanism, which could be affected by manipulating the expression of XOR (38
). Our data suggest that elevated concentrations of uric acid may reduce expression of XOR and attenuate PPAR-γ–dependent endocrine regulation in adipocytes.
In summary, uric acid can affect adipocytes directly by inducing effects resembling those observed in obesity: upregulation of proinflammatory factors and downregulation of the production of the insulin sensitizer and anti-inflammatory factor adiponectin via redox-dependent mechanisms, which can be prevented by an agonist of PPAR-γ (). In the mouse model of the metabolic syndrome, we observed hyperuricemia, which progressed with an increase in body weight. Lowering uric acid by inhibiting xanthine oxidoreductase in obese mice with the metabolic syndrome could improve the proinflammatory endocrine imbalance in the adipose tissue by lowering production of MCP-1 and increasing production of adiponectin.
FIG. 8. Model for the effect of hyperuricemia on the endocrine balance in adipocytes. This model summarizes the results of the current and the previous (15) studies. Uric acid can enter adipocytes through a uric acid–specific transporter. We identified (more ...)