Brain meets body: the blood-brain barrier as an endocrine interface

Abstract

The blood-brain barrier (BBB) separates the central nervous system (CNS) from the peripheral tissues. However, this does not prevent hormones from entering the brain, but shifts the main control of entry to the BBB. In general, steroid hormones cross the BBB by transmembrane diffusion, a nonsaturable process resulting in brain levels that reflect blood levels, whereas thyroid hormones and many peptides and regulatory proteins cross using transporters, a saturable process resulting in brain levels that reflect blood levels and transporter characteristics. Protein binding, brain-to-blood transport, and pharmacokinetics modulate BBB penetration. Some hormones have the opposite effect within the CNS than they do in the periphery, suggesting that these hormones cross the BBB to act as their own counterregulators. The cells making up the BBB are also endocrine like, both responding to circulating substances and secreting substances into the circulation and CNS. By dividing a hormone's receptors into central and peripheral pools, the former of which may not be part of the hormone's negative feed back loop, the BBB fosters the development of variable hormone resistance syndromes, as exemplified by evidence that altered insulin action in the CNS can contribute to Alzheimer's disease. In summary, the BBB acts as a regulatory interface in an endocrine-like, humoral-based communication between the CNS and peripheral tissues.

Figures

Fig. 1.

Mechanisms for translocation across the BBB of hormones and their messages between the brain and blood. The role of barrier prevents substances from crossing the BBB as exemplified by steroids that are protein bound. Permeability of the BBB is often by way of transmembrane diffusion as exemplified by unbound steroid hormone or by way of transporters as exemplified by leptin. The cells forming the BBB are themselves targets of circulating substances as exemplified by the many effects that insulin has on brain endotheial cell function. The cells that form the BBB are themselves endocrine-like in that they can secret substances into the blood or into the brain as exemplified by IL-6 secretion by brain endothelial cells. Relay is a special feature arising from the unique separation of brain endothelial cells into luminal and abluminal membranes and allows the BBB cell to receive an input on one membrane and to secrete from the other as exemplified here by adiponectin acting at the luminal membrane to alter secretion of IL-6 from the abluminal membrane. Extracellular pathways (data not shown) can be used by albumin and by very large and stable proteins (antibodies, erythropoietin) to gain access to the CNS.

Fig. 2.

Hormones crossing the BBB can modulate their peripheral affects. A hormone crossing the BBB can reinforce its peripheral actions by inducing its release from central stores (illustrated in the left panel by TNF) or by other mechanisms such as vagal relay (illustrated in the middle panel by insulin action on gluconeogenesis). A hormone crossing the BBB can attenuate its peripheral actions as exemplified in the right panel by insulin's effects on feeding.