Dynamic regulation of leptin entry into brain by the blood–brain barrier
Section snippets
Overview
Leptin has not yet fulfilled its promise as the magic bullet of obesity, partly because of ‘leptin resistance’. Leptin resistance, in which high levels of leptin in the blood of obese people and rodents do not reach the brain, could be explained by a defect of leptin crossing the blood–brain barrier (BBB).
The BBB is mainly composed of specialized endothelial cells of cerebral capillaries which are devoid of fenestrations or transendothelial channels and are joined by tight junctions. The
Leptin resistance
It is the concentration of leptin in the CNS, not in the periphery, that correlates with the reduction of body weight. Since leptin is mainly synthesized by adipose tissue in the periphery, limitation of the blood-to-brain transport of leptin has been hypothesized to explain the obesity referred to as leptin resistance. In obesity, increased concentrations of leptin in blood fail to reduce food ingestion [13], [14], [15], [16], [17]. This is reflected in the decreased ratio of blood to CSF
Multiple-time regression analysis
Multiple-time regression analysis [25] has been the most frequently used method for study of the influx into brain of bioactive peptides and proteins having relatively low penetration across the BBB. This technique is based on a mathematical model originally generated by Patlak, Blasberg and Fenstermacher [26], [27]. In this method, radiolabeled leptin is given to the anesthetized animal in an intravenous bolus injection, and the radioactivity of leptin in blood and CNS is measured
Mice
The entry rate (Ki) of [125I]leptin after i.v. injection in mice is 5.87×10−4 ml/g min, significantly greater than that for [99mTc]albumin [10]. Inclusion of 1 μg/mouse of unlabeled leptin in the injection decreases the Ki by 93% to 0.36×10−4 ml/g min, showing the self-inhibition characteristic of a saturable transport system. Inhibition of the transport of [125I]leptin by unlabeled leptin is dose-dependent. Saturation appears to be highly selective; we have tested a large number of ingestive
Further studies of saturation: roles of age, weight, and adiposity
With saturation of a transport system, an excess amount of the substance to be transported does not enhance the rate of influx. This excess could occur when the endogenous concentration of leptin in blood is increased. As with insulin, levels of leptin in blood are correlated with body weight, increasing with obesity [44]. A confounding factor, however, is the age of the study subject, as the concentration of leptin may decrease with aging [44].
In a study of mice of different ages and weights,
Body fat: direct or indirect effects?
An increase in body fat could affect the transport of leptin across the BBB in at least two main ways: self-inhibition of the transport system by increased production of leptin and neuroendocrine modulation. Increased adiposity, rather than aging or increased non-fat body mass, is a major factor in decreasing the entry of leptin into the brain [45]. Despite this direct effect, adipose tissue also might cause endocrine changes that indirectly affect the transport system. In a preliminary study,
Conclusions
Although all the factors controlling the blood-to-brain transport of leptin across the BBB have not been determined, it is clear that there is a transport system for leptin that is saturable and therefore susceptible to physiological and pharmacological manipulation. The results with leptin also serve to emphasize the dynamic regulatory role the BBB can play, even with molecules as large as the polypeptide leptin.
Acknowledgements
Supported by NIH (DK54880) and the VA.
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