BLOOD/BRAIN BARRIER AND LEPTIN TRANSPORT IN OBESITY

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DESCRIPTION: (Applicant's abstract) Leptin, a peripherally produced polypeptide, causes weight loss after crossing the blood-brain barrier (BBB) to enter the brain where it is considered to exert a major regulatory function in obesity. Paradoxically, in obesity blood levels of leptin are increased, resulting in what has been called "leptin resistance," accompanied by relatively low levels of leptin in the cerebrospinal fluid (CSF). It has been proposed that the mechanism causing this "resistance" is decreased passage of leptin across the BBB by the transport system we have described in non-obese animals. Here, we shall use well-established techniques to determine the pharmacokinetics of the transport of leptin across the BBB in rodents with dietary, genetic, and lesioned obesity. Quantification will involve multiple-time regression analysis and perfusion. HPLC will ensure that the material entering the brain is intact and capillary depletion, with washout, will ensure that leptin does not remain bound to the endothelium. Albumin will be co-injected to correct for leakage and non- specific passage. Saturability, the self-inhibition of transport, will be determined with unlabeled leptin. Autoradiography with quantitative image analysis will determine in obese animals the sites of localization of the leptin transporters, which will be isolated and identified, and their activity (energy and ion dependence) determined in cerebral endothelia cells. Preliminary results already support our hypothesis that the transport of leptin across the BBB is decreased in some forms of obesity. Although this defect might not explain all forms of "leptin resistance" in obesity, the transport system for leptin across the BBB does provide an appropriate target of regulatory control that is susceptible to experimental and eventual therapeutic manipulation.