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Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center-St. Louis, St. Louis, Missouri 63106; and Department of Internal Medicine, Division of Geriatrics, St. Louis University School of Medicine, St. Louis, Missouri 63104
Address all correspondence and requests for reprints to: William A. Banks, Veterans Affairs Medical Center (VAMC), 915 North Grand Boulevard, St. Louis, Missouri 63106. E-mail: bankswa{at}slu.edu.
The decade of the 1880s saw huge tracts of Africa and Asia come under the influence of the European powers. These "spheres of influence" promoted internal trading and commerce and created barriers to trade outside the sphere. It was in this decade that a young Paul Erlich, who later won the Nobel prize for his work on antibiotics, made the observation that some dyes injected into the bloodstream did not stain the brain. Eventually, this work formed one of the chief proofs that a barrier existed between the brain and the blood (1). Hence, it seemed the body also had its spheres of influence and a blood-brain barrier (BBB) that denied a trade of molecules between the blood and the brain.
A century later, fast air travel and faster electronic communications foster a world philosophy that emphasizes a connectedness and strives toward ever-freer communication among the nation-states. But the geopolitical climate still struggles with the legacy of an Imperialist past, whose tenets are now largely denied. Likewise, the BBB is emerging as a regulatory interface, rather than as an absolute barrier, by virtue of its ability to control, rather than totally deny, a trafficking of peptides and regulatory proteins between the blood and brain. But the BBB also struggles with its scientific legacy. Most scientists whose primary field is not the BBB still have a view of an absolute barrier that has only two pathophysiological states: disrupted or not disrupted. However, it is here that the analogy between politics and science ends. Instead of denying its barrier past, the field of BBB builds on it. Being a restrictive barrier allows the BBB to selectively control the exchange of regulatory molecules between the sphere of the body and the sphere of the central nervous system. It is this dualism of barrier and regulatory interface that makes the study of the BBB so especially exciting at this point in its long history.
No area better exemplifies this dualism than that of the gastrointestinal hormones. By the late 1970s it was clear that many of the peptides found in the gut were also found in the brain (2, 3). This gave rise to the term "gut-brain axis." But the mechanisms that powered this axis were unclear, as it was an untested assumption that these peptides would be too large to cross the BBB. Insulin was one of the few peptide hormones whose interaction with the BBB had actually been examined. Two studies conducted in 1954 had concluded that insulin could not cross the BBB. However, Margolis and Altszuler (4) used the newly developed technique of RIA to revisit this question in 1967. They found insulin in the cerebrospinal fluid, and its nonlinear relation with serum insulin suggested that it was transported across the BBB by a saturable system. Woods, Porte, and colleagues published a series of papers starting in 1977 (5) that confirmed and extended this work. However, the idea that insulin could cross the BBB was contested in the literature for at least a full decade after Woods and Porte began their work. The counter literature at first denied that insulin was present in the cerebrospinal fluid and later, after conceding its presence there, held that the brain, not the blood, was the source. As the view that the central nervous system produced little or no insulin took hold, the importance of the work showing insulin in the cerebrospinal fluid became increasingly appreciated (6).
In the meantime, work investigating the question of whether other peptides could cross the BBB was developing techniques that could quantify rates of entry into the brain, address mechanisms of passage, and investigate the influence of physiological and pathological events. These techniques rely heavily on radioactively labeled peptides and so side-step issues such as tissue of origin while providing a high level of sensitivity. It is the state-of-the-art version of these techniques that the paper of Yu et al. (7), in this issue, uses to investigate the interactions of the BBB transporters for IGF-1 and insulin.
The work of Yu et al. (7) builds on some fascinating background. It is now clear that not only is insulin transported across the BBB by a saturable system, but so are a host of other "gut-brain" peptides and regulatory proteins (8, 9). Leptin, ghrelin, pancreatic polypeptide, IGF-I, and some of the proinflammatory cytokines are examples of other substances that cross the BBB. These transporters are not static, but are responsive to peripheral events and the needs of the brain. The transporters are also affected by pathology and may even produce disease when they malfunction (10). For example, impaired function of the transporter for leptin occurs early in obesity and is the chief cause of leptin resistance in the early stages of obesity (11).
The insulin transporter likewise shows some fascinating responses. It is likely overexpressed in the neonatal period (12) and is shut off during hibernation (13). Transport is enhanced in insulinopenic diabetes (14), inhibited in obesity (15, 16, 17), impaired by hyperglycemia (14), and increased in the proinflammatory state induced by treatment with lipopolysaccharide (18). Many of these responses make sense when brain insulin is viewed as a counterregulatory hormone to blood insulin (19). Insulin administered into the brain, for example, inhibits feeding, increases serum glucose, and reduces serum insulin levels; all these effects are opposite to those of peripherally administered insulin. Although in the short-term these effects should produce a kind of insulin resistance, suppression of feeding and protection against obesity seem to be the predominant long-term effects of central nervous system insulin (20).
As the numbers of and roles for BBB transporters of peptides and regulatory proteins increase, the question of whether these transporters interact arises. It is already known, for example, that insulin modulates (21), but is not transported by (22), the transporter for leptin. A hallmark of BBB transporters for small molecules is that they transport classes of substances rather than just individual substances. For example, the amino acid tryptophan uses a transporter used by other large neutral amino acids, and glucose uses a transporter for hexoses (23). It is unclear whether peptide and protein transporters at the BBB will be specific for their ligands or selective for classes of ligands. So the question must arise whether the insulin transporter, like the insulin receptor, also interacts with IGF-I. The work of Yu et al. (7) shows that insulin and IGF-I have separate transporters, although they to some extent can share each others ligands.
The work of Yu et al. (7) illustrates another principle that is increasingly dominating the thinking of BBB-mediated brain-body interactions. The concept of the neurovascular unit emphasizes the interactions of the brain endothelial cells that comprise the BBB with neurons, astrocytes, glia, and pericytes. Immune cells and carrier proteins are examples of blood-borne elements that also affect BBB permeability. Here, carrier proteins influenced not only the permeation of IGF-I across the BBB but also the ability of IGF-I to interact with the insulin transporter. Thus, modulation of BBB transporters and control of brain levels of insulin and IGF-I can result from peripheral events that at first may seem to have little to do with the ultimate neurological endpoints.
Overall, the work of Yu et al. (7) exemplifies the new era of understanding that underlies the mechanisms of communication between peripherally secreted hormones and events in the brain. The BBB should no longer be viewed as a simple, absolute barrier that denies the entry of peptides and regulatory proteins into the brain. Rather, it is a complex, dynamic interface that balances the dual functions of barrier and transportation. The transporters are not static, but respond to and influence peripheral and central events. Transporter dysfunction can itself lead to disease. These extrabarrier aspects of the BBB provide a humoral mechanism that is a driving force of the gut-brain axis.
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Abbreviation: BBB, blood-brain barrier.
Received March 14, 2006.
Accepted for publication March 15, 2006.
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