Rationale Epidemiological studies link higher serum phosphate and the phosphatonin fibroblast growth factor (FGF) 23 with cardiovascular events and atheroma, and lower serum phosphate with insulin resistance and the metabolic syndrome. However, no direct evidence exists to prove whether either of these associations is causal. We sought to determine whether manipulating dietary phosphate influences either atherogenesis or insulin sensitivity in mice.

Methodology and Results Apolipoprotein E knockout (ApoE−/−) mice were fed a Western (atherogenic) diet with low (0.2%), standard (0.6%), or high (1.6%) phosphate content. Serum phosphate and FGF 23 significantly increased with increasing dietary phosphate intake, while calcium decreased. Lipid profile and blood pressure were unaffected. After 20 weeks, mice on the higher phosphate diet had significantly more atheroma at the aortic sinus (42±1.9% vs 30±1.5% for high vs low dietary phosphate, p<0.01) but with no evidence of calcification. Compared with standard and high phosphate diet groups, mice on a low phosphate diet had more adipose tissue (epididymal fat pad mass 84±23 mg vs 19±8 mg for low vs high phosphate group, p<0.05) and a marked increase in insulin resistance measured by homeostatic model assessment (HOMA-IR, 43.7±9.3 vs 11.1±0.8 and 8.9±0.7 for low vs medium and high, p<0.005).

Conclusions A high phosphate diet accelerates atherogenesis in ApoE−/− mice, while low phosphate intake induces insulin resistance. These data indicate for the first time that controlling dietary phosphate intake may influence development of both atherosclerosis and the metabolic syndrome.