1958-P: Role of Leptin in Blood-Brain Barrier Dysfunction

All forms of diabetes mellitus are characterized by chronic hyperglycemia resulting in the development of a number of microvascular and macrovascular pathologies. Diabetes is also associated with changes in brain microvasculature leading to dysfunction and disruption of the blood-brain barrier (BBB). These changes are correlated with a decline in cognitive function. The BBB is a regulatory interface between brain and blood, preventing the unrestricted leakage of plasma proteins into the central nervous system (CNS) and performing nutritive, homeostatic, and communication roles. Studies have shown that in a streptozotocin-induced mouse model of type 1 diabetes, where insulin and leptin levels are low, BBB dysfunction occurs in five brain regions: frontal cortex, occipital cortex, parietal cortex, midbrain, and thalamus. In contrast, in a diet induced obese (DIO) model of type 2 diabetes, where insulin and leptin levels are high, BBB dysfunction did not occur in those five regions but did occur in the hippocampus and hypothalamus. In both models, all mice were hyperglycemic, indicating that this is not the only mechanism by which BBB dysfunction occurs. To further investigate the role of the hormones leptin and insulin in BBB dysfunction, we utilized the BTBR.Cg-Lep^ob/WiscJ ob/ob mice, a transgenic model of type 2 diabetes where insulin is high and no leptin is present. Using radioactively labeled ligands, we have demonstrated that loss of leptin leads to BBB dysfunction in all brain regions as early as four weeks of age. Importantly, these mice are not born with this dysfunction as studies in two-day old pups demonstrate an intact BBB. Replenishment of leptin to these BTBR.Cg-Lep^ob/WiscJ ob/ob mice from birth was able to attenuate BBB dysfunction observed at four-weeks of age. These studies indicate that leptin is a key component in maintaining BBB integrity in diabetes.