In 1979 Mutt et al showed that secretin when injected directly into the brain could induce pancreatic secretions at a fraction of its peripherally effective dose [11
]. Thus, secretin joined the ranks of a growing number of substances originally identified in the periphery but with effects within the brain. Currently, this rank includes a long list of substances, including insulin, leptin, ghrelin, amylin, and pancreatic polypeptide. To exert their actions at receptors deep within the brain, these substances must cross the BBB. Many of these substances in this class, not surprising, have been shown to have saturable transporters located at the BBB, whereas some of the others can cross by non-saturable mechanisms. What these substances do within the brain once they have occupied their CNS receptors is not always clear. Some, such as leptin, exert what is currently thought to be their main actions within the CNS. Others, such as insulin, can have effects opposite to those that they exert in the periphery [12
]. For example, peripheral administration of insulin will raise blood levels of insulin, reduce levels of glucose in the blood, and stimulate feeding, whereas administration of insulin into the brain has been reported by several laboratories to reduce blood levels of insulin, increase levels of glucose in the blood, and inhibit feeding. Therefore, substances like insulin which oppose through the CNS their peripheral actions may act as their own counterregulatory hormones [14
Some substances produced in both the brain and the periphery are able to cross the BBB. Why a peptide or protein that is produced in the brain is also transported into the brain is not clear. It may be that the transported material accesses a different set of receptors than material endogenous to the CNS, reinforces only selected concentrations of endogenous material, or can form different concentration gradients in combination with endogenous material across a network of receptors.
Transport patterns across the BBB can provide hints at what are some of the actions of these substances within the CNS. For example, whereas most of the work on the CNS actions of leptin, ghrelin, and to a lesser extent insulin have concentrated almost exclusively on the hypothalamus, these substances have BBB transporters and CNS receptors located throughout the CNS [15
]. Evidence shows that in each case these extra-hypothalamic brain receptors are operational and affect CNS functions [18
]. Furthermore, each of these substances have BBB transporters and neuronal receptors located at the hypothalamus and can exert profound effects on cognitive functions. Therefore, it is likely that gastrointestinal hormones have multiple roles within the CNS.
Another example of BBB transport patterns providing insight into function is the finding that the majority of insulin entering the brain from the periphery does so at concentrations lower than those needed to induce hypoglycemia [21
]. Therefore, it is unlikely that CNS insulin acts primarily to inform the brain about potential hypoglycemia. Instead, it is likely that most of the information the brain gathers from the transport of insulin relates to physiological events. However, insulin transport is likely also to be involved in certain pathological reactions. Animals treated with lipopolysaccharide, a derivative of the cell walls of gram negative bacteria and a potent inducer of the innate immune system, increases insulin transport 2-3 fold [23
]. To the extent that CNS insulin acts in a counterregulatory fashion to blood insulin, an increase in CNS insulin would induce resistance to the peripheral actions of insulin. Release of lipopolysaccharide by gram negative bacteria could increase transport of insulin across the BBB and so induce the insulin resistance seen in sepsis [24
Leptin transport patterns provide several clues to the function, role, and evolution of leptin. Inhibition of leptin transport in obese animals is consistent with the development of leptin resistance at the level of the BBB [26
]. The studies also show that the blood-to-brain signal of leptin to the brain is most robust at leptin levels below those considered to represent ideal body weight [27
]. This, in turn, suggests that leptin evolved to be most effective at what in Western societies are low to low-normal levels. Interestingly, wild baboons living in normal, non-famine conditions also have low levels of leptin, suggesting that during most of evolution, lower levels of body fat and much lower levels of leptin were the norms [28
]. We have found that part of the inhibition in leptin transport associated with obesity is caused by circulatory factors in addition to leptin itself and part of the inhibition is not explained by the immediate effects of circulatory substances [29
]. Triglycerides inhibit leptin transport across the BBB and, since triglycerides tend to be high in obesity, are likely one cause of leptin resistance [30
]. However, triglycerides are also high in starvation. Blockade of the anorectic leptin during starvation would convey survival value. Since animals and humans have more often been faced with starvation than obesity, it is likely that triglycerides came to represent to the CNS starvation, not obesity. In this sense, the leptin resistance of obesity as caused by hypertriglyceridemia may be a metabolic case of mistaken identity because of an unfortunate coincidence that hypertriglyceridemia occurs in both obesity and starvation.