Year: 2010
Type: article
Abstract: The body weight thing is obviously hard to get right. Whereas many Westerners battle obesity in the younger years, later life is often vexed with anorexia of aging, a condition in which the elderly lose massive amounts of weight (1). Whereas anorexia has remained a difficult problem to treat, there are many thyroid hormone-, serotonin-, and adrenergic-based drugs that can induce tremendous losses in body weight. Unfortunately, those drugs when used for weight loss have unacceptable rates of morbidity and mortality. The difficulties in controlling body weight likely begin deep within ancestral genes. To paraphrase Ernst Mayer, no biological problem can be fully understood until it is placed in its evolutionary context (2). Studies of paleolithic diets show that our ancestors were chronically short of three important food items: salt, simple carbohydrates, and fats. Reproductive success, the engine that drives evolution, favored strategies and behaviors that resulted in increasing these components in the diet. Likewise, reproductive success likely benefited little from strategies and behaviors that sought to limit intake. Hence, in a modern world in which sodium chloride, sugars, and fats are abundant, there is a natural tendency to overconsume them, producing an affluent malnutrition that results in epidemic levels of hypertension, obesity, and type 2 diabetes mellitus (3). On a positive note, our understanding of the drivers of appetite has increased tremendously in recent years (4). Ultimately body weight is determined by a simple arithmetic that is a balance of calories consumed minus calories expended. However, the calculus behind what drives appetite and influences food choice, what dictates the level of caloric expenditure, and what those calories are spent on is far from simple. Indeed, there are so many small molecules, peptides, and regulatory proteins involved in feeding that this alone would signal that the ultimate decision to feed or not to feed is far from simple. The evolutionary perspective again is helpful. Unlike Western man and his pets, animals living in the wild must rationally or intuitively make a large number of cost/benefit decisions regarding feeding (5, 6). Examples include the following: will more calories be expended than gained in the hunt for food; what is the probability of becoming prey or suffering injury in the attempt to acquire calories; what food sources are likely to be most productive given current conditions of weather, temperature, or season; and is it more profitable to search for food or steal it from others? Likewise, when food is scarce, the body must make decisions about which energy-demanding activities to attenuate and which to support. For example, the high caloric demands of activating the immune system can often result in an animal with low caloric reserves dying not from infection but from starvation (7). Interestingly, activation of the innate immune system induces sickness behavior, a complex of adaptive changes in behavior and physiology that can help to conserve caloric resources (8). It is increasingly clear that the decisions about feeding and caloric expenditure are not made by the tissues themselves but by the central nervous system (CNS). Yet it is the peripheral tissues that acquire and digest the food and store the calories. Hence, the obvious need for communication between the CNS and the peripheral tissues is fundamental (9). This communication is bidirectional with signals traveling both to and from the CNS. Communication occurs by routes both neural and humoral (10). The complexity of this communication is exemplified from the large number of hormones being discovered to be secreted from adipose tissue (11). Hormonal communication between peripheral tissues and the CNS, however, faces an extra complexity usually not seen in hormonal communication among peripheral tissues. The hormones are not able to leak out of the capillary bed into the interstitial fluid of the brain because the microvessels of the CNS are specially modified to form the blood-brain barrier (BBB). However, this is not the end of the story. The BBB is endowed with numerous transporters (modern estimates suggest that only 10% of BBB transporters are so far discovered), including those dedicated to the transport of feeding-related peptides and regulatory proteins. It is clear that these transporters are not static but change with physiologic demands and under the pressures of disease. However, the degree to which these changes might occur, under what circumstances, and by what mechanisms are far from clear. The paper by Hsuchou et al. (12) published in the current issue of Endocrinology pushes our fundamental understanding of these issues into some interesting new directions. Previous work by this group has shown that urocortin transport across the BBB is highly inducible. Indeed, urocortin transport across the BBB of the adult does not occur but can be induced by leptin or TNF-α (13, 14). Here the investigators found that urocortin transport is the norm in the neonatal BBB but disappears in the adult. This raises intriguing questions about the early cross talk between the developing CNS and peripheral tissues. Regulatory systems in the CNS often undergo critical periods when alterations in peripheral signals can alter responses in the adult. A classic example is the treatment of neonates with opiate peptides, which can result in alterations in pain perception as an adult (15). Fibroblast growth factor crosses the BBB of the neonate to increase neurogenesis (16), and many of the classic gastrointestinal peptides, including ghrelin and glucagon-like peptide-1, also affect neurogenesis (17–19). This then raises the question of whether urocortin derived from peripheral tissues is involved in a programming of the CNS during the neonatal period. This would not be the first instance in which differences in the neonatal BBB resulted in long-term effects on feeding and body weight. A specialized arm of the BBB, a barrier of tanycytes between the median eminence and the hypothalamus, develops in rodents in the postnatal period (20). The median eminence is a part of the brain in which the BBB does not form and so the capillaries are leaky. In the neonatal rodent, monosodium glutamate can leak from blood into the median eminence and then diffuse into the hypothalamus, destroying the arcuate nucleus and inducing obesity. The tanycytic barrier in the adult prevents the diffusion of glutamate out of the median eminence and so protects the hypothalamus. This barrier, of course, prevents the much larger regulatory proteins, such as leptin and IL-1, from leaking out of the median eminence into the hypothalamus (21). As such, these substances must cross the BBB through their specific, saturable transport systems. Unlike leakage, transporters can be regulated and are responsive to changes in physiology (22, 23). When these transporters or their regulatory mechanisms fail, diseases can arise as in the case of leptin transport and obesity (24). The neonatal BBB is, however, mature in the sense that it is as restrictive to the leakage of serum proteins from the blood into the brain as is the adult BBB (25, 26). Permeability of the neonatal BBB and adult BBB are also nearly identical with lipid soluble substances (27). The differences between the neonatal and adult BBB are largely thought to be in response to the differences in the needs of a developing vs. a mature CNS. In other words, the BBB adapts to the needs of the maturing CNS. What change in the CNS shifts the activity of the urocortin transporter from being constitutive to inducible is a mystery. The work of Hsuchou et al. (12) addresses another fundamental problem that is largely overlooked by the feeding field, which is the identity of the transporters. It is widely assumed, for example, that the short form of the leptin receptor is the BBB transporter. However, the Koletsky rat has no functional leptin receptors (28) yet is able to transport leptin from blood to brain (29). Furthermore, megalin appears to be the protein responsible for transport of leptin from blood to cerebrospinal fluid (30). The work by Hsuchou et al. (12) presents circumstantial evidence that the CRH receptor, CRH receptor-1, is the BBB transporter for urocortin. However, expression of CRH receptor-1 is still present in the adult brain endothelial cell at a time when urocortin transport is not occurring across the BBB. Overall, the work by Hsuchou et al. (12) reminds us that the BBB is the gatekeeper to the brain, controlling the flow of information between the CNS and peripheral tissues by excluding many informational molecules and controlling the access of others. This work also reminds us that the BBB is not static but is itself intimately in tune with the needs of the CNS and responding to the changing demands of the developing brain. Blood-brain barrier; central nervous system.
Source: Endocrinology
DOI: 10.1210/en.2009-1442
Author: William A. Banks
Institutions: St. Louis VA Medical Center, Saint Louis University
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W1963948588