The blood-brain barrier (BBB) has been recognized for almost a century as gatekeeper for the neuronal internal milieu. It specifically appears as a pivotal point in the communication between the brain and peripheral endocrine tissues. Thus, the BBB controls the entry of major metabolic hormones into the brain from the blood, including the adipocyte-derived hormone leptin (1). Importantly, impaired transport of leptin across the BBB is considered as one of the major causes of leptin resistance and associated obesity (2, 3). A report in this issue of Endocrinology (4) reveals that the BBB and its capacity to transport leptin differs in the neonate from that in the adult and provides novel insights into the control of leptin transport to the brain.
In addition to regulating energy balance and neuroendocrine functions in mature animals (5), growing evidence indicates that leptin also plays a critical role in brain development. Elevated levels of leptin are found particularly during the first 2 wk of life in rodents (6) at a time when leptin is largely ineffective at altering body weight or food intake (7, 8). Interestingly, this neonatal surge in leptin (6) appears to coincide with the development of major hypothalamic feeding circuits (9). Neuroanatomical experiments further revealed that instead of acting as a metabolic regulator, neonatal leptin acts as a trophic factor promoting development of hypothalamic circuits controlling energy homeostasis (10). The neurodevelopmental actions of leptin are not restricted to the hypothalamus because cortical and hippocampal development can also be influenced by leptin (11, 12).
In adults, leptin crosses the BBB by receptor-mediated transport, and the short form of the leptin receptor (ObR), ObRa, is considered as one of the main transporters for leptin across the BBB (13, 14). Despite the established role of leptin in brain development (10, 11), little is known about developmental aspects of leptin transport to the brain. The studies by Pan et al. (4) in the current issue of Endocrinology examine the developmental changes in expression of ObRs in brain microvessels and compares them with leptin transport across the BBB. The authors found that ObR expression is developmentally regulated in brain microvessels with both the short (ObRa), the long (ObRb), and the soluble (ObRe) isoforms being expressed at higher levels in neonates than in adults (Fig. 1). These observations logically led the authors to hypothesize that leptin transport might be increased during postnatal life. Surprisingly, analysis of leptin transport across the BBB revealed that transport of the hormone is actually reduced in the brain of neonates compared with that of adults (Fig. 1).
Highly simplified schematic outlining possible mechanisms that mediate leptin transport into the brain of postnatal and adult animals. In adults, the short form of ObR (ObRa) likely mediates transport of the hormone from the microvessels to the brain. In contrast, this receptor does not seem to be the main limiting factor of leptin transport across the BBB in neonates. Despite elevated levels of plasma leptin and increased levels of ObRa expression, reduced transport of leptin is observed during development. An increased antagonistic action of the soluble form of ObR (ObRe) may be a cause of the reduced leptin transport. Once in the brain, leptin reaches neurons containing the long form of ObR (ObRb) to induce its regulatory and developmental actions.
The study by Pan and colleagues (4) elegantly supports the idea that the BBB is not static but is modulated by several physiological conditions. Although previous studies showed that conditions such as obesity or fasting are associated with changes in BBB permeability (2, 3, 15), this is the first report addressing the dynamic of leptin access to the brain during development. Moreover, this study postulates potential unique mechanisms mediating leptin transport into the brain during development. In sharp contrast to adults, ObRa does not appear to be the main regulator of leptin transport in the neonatal brain. Although the identity of this transporter remains undetermined, the findings by Pan et al. (4) raises the exciting possibility that other undiscovered proteins may also act as leptin transporters, especially during early postnatal life. Alternatively, and as suggested by the authors, the decreased leptin transport observed in neonates might also be caused by increased antagonistic activity of the soluble form of ObR (ObRe) (Fig. 1). ObRe is a binding protein produced by both neuronal and endothelial cells and acts as an endogenous antagonist of leptin (16). Therefore, the elevated levels of ObRe expression found in neonates may participate in the reduced leptin transport observed during development.
Like most new and exciting observations, the current study prompts many additional questions. For example, if ObRs do not act primarily as transport systems for leptin during neonatal life, then what is the role of these receptors? One possibility is that the presence of ObRa (and ObRb) in brain microvessels during development instead may be related to leptin’s action as an angiogenic factor. Consistent with this idea, leptin has been found to induce angiogenesis, and this effect is mediated, at least in part, through ObRb activation (17). Equally interesting is the observation that brain vasculature expands significantly during the occurrence of the postnatal leptin surge, which suggests that the postnatal leptin surge would not only induce formation of neural circuits but also regulate vascular development.
At a time when childhood obesity is reaching epidemic proportions, it appears crucial to better understand the biological processes mediating development of metabolic systems. Recent publications are now providing strong support for the functional importance of leptin during development, including a role in hypothalamic development (10) and in programming the later metabolic fate of the organism (18, 19). The findings by Pan et al. (4) add some important missing pieces of this puzzle and improve our understanding of how leptin reaches its targets at a time when this hormone exerts its maximal effect on brain and metabolic development. The possibility that distinct mechanisms mediate leptin transport across the BBB in postnatal and adult life is an exciting prospect that may lead to innovative new strategies for treatment for obesity.
See article p. 877.
Acknowledgments
Disclosure Statement: The author has nothing to disclose.
