Current Pharmaceutical Design - Volume 9, Issue 10, 2003

The blood-brain barrier (BBB) plays a crucial role in the regulation of body weight and feeding by peptides. This review summarizes the components of the BBB as well as the circumventricular organs (CVOs), the methods used for quantification of the passage of feeding peptides across the BBB, and the various ways by which these peptides can interact with the BBB.

Although several possible mechanisms exist by which the pancreatic hormone, insulin, could enter the brain from the blood, most evidence suggests that the majority of it enters primarily by a receptor-mediated transport process. Many factors influence the rate of entry, including fasting and refeeding and several pathological conditions. Within the brain insulin acts on specific receptors to influence a number of behaviors, and especially caloric homeostasis and cognition.

Leptin has emerged as a major regulator of body adiposity. The majority of humans with obesity have a resistance to leptin. Human and rodent studies indicate that the major cause of this resistance arises from an impaired ability of leptin to cross the blood-brain barrier, with lesser roles played by receptor and post-receptor defects. Evidence from baboons living in the wild is consistent with the hypothesis that during most of evolution serum levels of leptin were much lower than those currently considered normal. Leptin may have evolved to signal to the brain when caloric reserves were adequate to engage in reproductive and other behaviors not immediately concerned with acquisition of calories. The leptin transporter is a regulated system, with the rate of transport being increased by alpha-1 adrenergic agents and decreased by starvation. Impaired regulation of the transporter or impairments in transporter production could underlie the resistance caused by transporter defects. Evolutionary pressures would not have selected against such impairments if leptin levels were lower than those typically seen in Western society. A model that could explain how leptin transporter resistance can be acquired is presented.

Leptin has been shown to have a wide repertoire of peripheral effects, some of which are mediated through the central nervous system and others that are induced through a direct action on target tissues. There is now evidence showing that leptin exerts some of its metabolic effects acting directly on peripheral tissues. The role of leptin has expanded from a narrow position in obesity to effects on biological processes, such as diabetes, appetite, thermogenesis, the immune system and reproduction. Here in a first part, we review preclinical evidence for direct effects on specific tissues (neurons, liver and muscle) and metabolic pathways. In a second part we review clinical evidence for leptin effects. In particular we review the effects of recombinant human leptin in lean, obese, diabetic subjects and in patients with congenital leptin deficiency or lipoatrophic diabetes. Additionally, while clinic leptin has not shown dramatic effects in obese / diabetic subjects with measurable serum leptin, in states of leptin deficiency treatment with leptin has been shown to have profound effects on body weight and appetite and insulin resistance.

Amylin is a 37-amino acid peptide hormone that is co-secreted with insulin by pancreatic B cells in response to food intake. Exogenous amylin potently and dosedependently reduces feeding in rats and mice, with both central and peripheral sites being effective. Although amylin has been characterized as a satiety signal that regulates short-term food intake (i.e., meal size), recent data indicate that amylin may have long term effects on food intake and body weight. In fact, amylin shares many properties with the established adiposity signals, leptin and insulin. Like leptin and insulin, amylin is not synthesized within the brain, but is rapidly and efficiently transported across the blood-brain barrier (BBB) to a variety of discrete brain regions, including the hypothalamus, where populations of amylin binding sites are found. Further, amylin secretion and plasma levels are correlated with the degree of body adiposity, as is the case for leptin and insulin. In the following brief review, a summary of the findings from recent reports is presented supporting the hypothesis that amylin's role in the control of food intake is not limited to that of purely a satiety signal that brings individual bouts of ingestion to an end, but also serves as an adiposity signal acting within the brain to regulate long-term energy homeostasis.

The blood-brain barrier (BBB) mediates interactions between the brain and the cytokines produced in the periphery. Some of these cytokines play significant roles in feeding behavior. This review will summarize various ways by which cytokines cross the BBB and discuss the implications of their transport systems in feeding. For simplicity of discussion, three categories of cytokines are discussed: (1) the proinflammatory cytokines TNFα, IFNγ, IL1, and IL6, (2) the chemokines MIP-1, CINC-1 and IL8, and (3) other cytokines (LIF, CNTF, GM-CSF, FGF, EGF, and TGFα). The pharmacokinetics of barrier penetration, compartmental distribution, stability, and mechanism of passage (presence or absence of saturable transport) are summarized. Our understanding of cytokines interacting with the BBB is still growing, not only are more cytokines being studied, but also more details of the nature of the transport systems and how they affect feeding behavior are being explored.

Diabetes mellitus is a metabolic disorder associated with structural and functional alteration of various organ systems including the central nervous system. The overall evidence suggests that the effect of Diabetes mellitus on the brain, although more subtle than some other chronic diabetic complications, is appreciable. A variety of pathogenetic mechanisms contribute to the central nervous system dysfunction in diabetic patient population. One major contributor is the Diabetes related alterations in the function of the blood-brain barrier (BBB). These alterations can be found in both barrier and transport components of the BBB function and can be attributed to changes in physicochemical properties of the endothelial cell membranes and of the tight junctions of the cerebral microvasculature. The present communication briefly reviews the Diabetes-related changes in the central nervous system and discusses some of the mechanisms underlying these changes.