Insulin in the brain acts as a satiety factor, reduces appetite, and decreases body mass. Altered sensing by brain of insulin may be a leading cause of weight gain and insulin resistance. A decrease in the transport across the blood-brain barrier (BBB) of insulin may induce brain insulin resistance by inducing obesity. We here report that transport of intravenously administrated insulin across the BBB of obese mice, as measured by multiple-time regression analysis, was significantly lower than that in thin adult mice. The reduction in obese mice was reversed by starvation for 48 hours. There were no differences in insulin transport rates across the BBB of obese, thin, or starved obese mice when studied by the brain perfusion model, demonstrating that BBB transport of insulin is modulated by circulating factors. In the brain perfusion study, the triglyceride triolein significantly increased the brain uptake of insulin, an effect opposite to that on leptin transport, in starved obese mice. Thus, circulating triglycerides are one of the systemic modulators for the transport of insulin across the BBB.