No abstract

Mucopolysaccharidosis type VII is a lysosomal storage disorder resulting from inherited deficiency of ␤-glucuronidase (GUS). Mucopolysaccharidosis type VII is characterized by glycosaminoglycan storage in most tissues, including brain. In these disorders, enzyme delivery across the blood-brain barrier (BBB) is the main obstacle to correction of lysosomal storage in the CNS. Prior studies suggested mouse brain is accessible to GUS in the first 2 weeks of life but not later. To explore a possible role for the mannose 6-phosphate͞insulin-like growth factor II receptor in GUS transport across the BBB in neonatal mice, we compared brain uptake of phosphorylated GUS (P-GUS) and nonphosphorylated GUS (NP-GUS) in newborn and adult mice. 131 I-P-GUS was transported across the BBB after i.v. injection in 2-day-old mice. The brain influx rate (Kin) of 131 I-P-GUS in 2-day-old mice was 0.21 l͞g⅐min and decreased with age. By 7 weeks of age, transport of 131 I-P-GUS was not significant. Capillary depletion revealed that 62% of the 131 I-P-GUS in brain was in brain parenchyma in 2-day-old mice. In addition, uptake of 131 I-P-GUS into brain was significantly reduced by coinjection of unlabeled P-GUS or M6P in a dose-dependent manner. In contrast, the Kin of 131 I-NP-GUS (0.04 l͞g⅐min) was significantly lower than 131 I-P-GUS in 2-day-old mice. Transcardiac brain perfusion confirmed that neither 131 I-P-GUS nor 131 I-NP-GUS crossed the BBB in adult mice. These results indicate that 131 I-P-GUS transport into brain parenchyma in early postnatal life is mediated by the mannose 6-phosphate͞insulin-like growth factor II receptor. This receptor-mediated transport is not observed in adult mice.␤-glucuronidase ͉ mannose 6-phosphate͞insulin-like growth factor II receptor ͉ central nervous system ͉ lysosomal storage disease ͉ phosphorylated ␤-glucuronidase

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 iv 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 h. 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.