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Laboratory of Molecular Endocrinology, Centre Hospitalier de l’Université Laval Research, Center and Department of Anatomy and Physiology, Laval University, Québec, Canada, G1V 4G2
Address all correspondence and requests for reprints to: Dr. Serge Rivest, CHUL Research Center & Laval University, 2705 Boulevard Laurier, Québec, Canada G1V 4G2. E-mail: Serge.Rivest{at}crchul.ulaval.ca.
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Introduction |
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Ordinarily, small capillaries are not permeable due the tight junctions and robust astrocytic foot processes, but penetrating arterioles and venules exhibit high degrees of variability that may give access to proteins, such as leptin. This hormone is produced mainly by the white adipose tissue and circulates into the bloodstream as a 167-amino acid protein with a relative molecular mass of 16 kDa (3). Such high molecular mass indicates that the protein has very limited access to the cerebral tissue through the regions that are more permeable or through selective penetrating arterioles or venules. The main target region of leptin is the ventrobasal hypothalamus just above the median eminence, the region where all neurosecretagogues are released into the hypophyseal-portal system (4). Median eminence is also a CVO equipped with a rich fenestrated vascular network extending to various subcellular regions of the arcuate nucleus. Therefore, direct interaction between leptin and its long-form receptor (Ob-Rb) expressed in neurons just adjacent to the median eminence remains a likely mechanism. However, leptin is also capable of activating neurons that are not adjacent to the median eminence, and the exact mechanisms explaining this phenomenon are still not clear at this point. In a recent paper published in this journal, Flier and colleagues (5) provided evidence supporting the existence of an active transport system via the leptin short-form receptor (Ob-Ra). They found high levels of both Ob-Ra and Ob-Rc transcripts in isolated rat cerebral microvessels and a decrease in brain uptake of leptin in mice lacking leptin receptor. The cerebral uptake of leptin was also reduced in diet-induced obese mice and in an animal model responding to central, but not peripheral, leptin (5).
In this issue of Endocrinology, Hosoi et al. (6) further support this concept and report that circulating leptin has the ability to trigger signal transduction events not only in the hypothalamus, but in different populations of neurons in the brainstem. Although it is not a cytokine, leptin receptor contains docking sites for Janus kinases (JAK) that phosphorylate specific members of the signal transducers and activators of transcription (STAT) family (7). Once activated, STAT proteins may activate different genes in combining their Src homology 2 domains and forming homodimers. Activation of JAK2 and STAT3 takes place in response to the binding of leptin with its transmembrane Ob-Rb. Both Western blot and immunocytochemistry techniques confirmed the presence of phosphorylated (p) STAT3 in the hypothalamus and brainstem, but not in the hippocampus, cortex, and cerebellum, of animals challenged with a single bolus of leptin (6). More specifically, positive pSTAT3 cells were found in the commissural and lateral part of the nucleus of the solitary tract (NTS) and in the superior and external lateral parts of the parabrachial nucleus and periaqueductal gray. Previous experiments using c-fos as a marker of neuronal activation reported similar data in these brainstem regions, and the double-labeling approach provided anatomical evidence that cholecystokinin neurons in the superior parabrachial nucleus and glucagon-like peptide-1 neurons in the NTS were activated by leptin (8). Although the nuclear protein Fos was detected in Ob-Rb-expressing cells in different hypothalamic regions, low Ob-Rb mRNA levels were found in the brainstem, and most Fos-immunoreactive nuclei failed to depict positive signal for the gene encoding the Ob-Rb (8). These data either suggest that leptin does not act directly onto these neurons, or in situ hybridization is not sensitive enough to detect Ob-Rb transcript in regions in which mRNA levels are less abundant. In this regard, the paper published in this issue found both Ob-Ra and Ob-Rb transcripts in the brainstem via RT-PCR (6).
These authors have also detected a 2.2-fold induction of the suppressor of cytokine signaling 3 (SOCS-3) mRNA in the hypothalamus and brainstem of leptin-injected mice (6). SOCS-3 belongs to family of inhibitory proteins, which are transcriptionally regulated by STATs following activation of the transduction signals (9, 10). These inhibitory intracellular proteins prevent phosphorylation of transcription factor STATs and activation of MAPKs by interacting with the catalytic domain of JAK kinases. The SOCS proteins are characterized by a highly conserved carboxyl-terminal SOCS box motif that is preceded by an Src homology 2 domain. Although it is not clear how SOCS-3 prevents JAK/STAT signaling, there is a rapid and strong transcriptional induction of the gene encoding this protein by cytokines that share the glycoprotein 130 receptor subunit. The presence of the Ob-Rb and induction of pSTAT3 and SOCS-3 in the brainstem suggest that circulating leptin triggers its transduction-signaling cascade in neurons involved in the control of autonomic functions. The question of how such a high-molecular-mass protein has access to these neurons is, however, still unanswered by these studies. Like the median eminence, an extensive network of capillary loops penetrates the area postrema, and the entire organ is exposed to hema milieu. Leptin may for this reason have access to NTS neurons that are anatomically associated with the area postrema—for instance, those immunoreactive for pSTAT3 in the commissural part (6). Such direct interaction is unlikely to occur in other brainstem regions, such as the parabrachial nucleus. It is also possible that circulating leptin targets neurons of the area postrema, which project to regions depicting c-fos and pSTAT3 signals. The presence of long-form receptor in this CVO supports this concept, but this organ failed to depict positive pSTAT3 cells in response to a single iv bolus of leptin (6). Finally, activation of NTS neurons could be mediated via vagal afferences that can be activated by leptin, especially in presence of cholecystokinin (11, 12).
It is nonetheless important to keep in mind that the paper published in this issue does not provide direct evidence that leptin crosses the BBB and targets neurons of the hypothalamus and brainstem. The JAK/STAT-signaling events and SOCS-3 transcription are induced by a wide variety of ligands that are either constitutively present or induced in different populations cells of the brain (13). So, circulating leptin may be able to stimulate the release these intermediate ligands at the level of the cerebral endothelium, CVOs, and choroid plexus. Although very different, this is the case for circulating lipopolysaccharide that causes the release of the cytokine IL-6 in these regions, which afterward diffuses freely across the cerebral tissue and triggers SOCS-3 transcription (14, 15, 16). It is also possible that the cerebral endothelium is more permeable than the current dogma, but this potential exciting, novel concept has yet to be firmly established with rigorous approaches, and this phenomenon is likely to depend on the types of blood vessels (penetrating arteriole, small capillaries, and venules), regions, and animal species. Integrity of the BBB is also altered during diverse physiological and pathological circumstances, and data generated in normal animals may not reflect the real situation taking place during pathological conditions. There is no doubt that circulating leptin activates specific populations of neurons in the hypothalamus and brainstem, but the mystery behind the transfer from blood to parenchymal elements has yet to be revealed.
Another example of possible transport system across the endothelium of the cerebral microvascular system is represented by the ability of circulating IGF-I to turn on postnatal neurogenesis in the dentate granule cell layer of the hippocampus (17). Indeed, systemic treatment with IGF-I is associated with an increase in newly generated neurons, and the growth-promoting peptide has, by some means, access to neuronal progenitor cells sitting within the parenchymal hippocampus (18). One can propose the existence of a sophisticated transport system in the microvasculature of dentate granule cell layer, but intermediate molecules may again explain the effects of systemically produced IGF-I on hippocampal precursor cells (19).
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Acknowledgments |
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Footnotes |
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Abbreviations: BBB, Blood-brain barrier; CVO, circumventricular organ; JAk, Janus kinase; NTS, nucleus of the solitary tract; Ob-Ra, leptin short-form receptor; Ob-Rb, leptin long-form receptor; p, phosphorylated; SOCS-3, suppressor of cytokine signaling 3; STAT, signal transducer and activator of transcription.
Received June 25, 2002.
Accepted for publication June 26, 2002.
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