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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online May 13, 2005 as doi:10.1096/fj.04-2384fje. |
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Department of Internal Medicine 1, Faculty of Medicine, Oita University, Hasama, Oita, Japan
1 Correspondence: Department of Internal Medicine 1, Faculty of Medicine, Oita University, Hasama, Oita 879-5593, Japan. E-mail: hiroy{at}med.oita-u.ac.jp
SPECIFIC AIMS
The present study demonstrates that: 1) corticotropin-releasing hormone (CRH) or hypothalamic neuronal histamine mediates the glucagon-like peptide-1 (GLP-1) -induced suppression of feeding behavior; 2) CRH mediates GLP-1 signaling to neuronal histamine; and 3) a functional link from GLP-1 to neuronal histamine via CRH constitutes the leptin-signaling pathway regulating feeding behavior.
PRINCIPAL FINDINGS
1. Effect of pretreatment with FMH or 
-helical CRH (-hCRH) on the GLP-1-induced suppression of food intake
The central infusion of GLP-1 significantly decreased the initial 1 h cumulative food intake compared with PBS controls. Intraperitoneal pretreatment with -fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase, partially attenuated the GLP-1-induced suppression of food intake. Administration of FMH alone did not affect the cumulative food intake compared with the PBS group (Fig. 1
). The GLP-1-induced suppression of food intake was abolished by pretreatment with -hCRH, a CRH antagonist. Treatment with -hCRH alone did not alter feeding compared with the PBS group.
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2. Effect of a central infusion of GLP-1 on the CRH, histamine, and tele-methyl histamine (t-MH) content in different hypothalamic nuclei
The central infusion of GLP-1 increased the CRH content in the paraventricular nucleus (PVN) and tuberomammillary nucleus (TMN) of the hypothalamus compared with PBS controls but not in ventromedial hypothalamic nucleus (VMH) and lateral hypothalamus (LH). Central administration of GLP-1 increased the histamine content in the TMN and increased pargyline-induced accumulation of t-MH, a major metabolite of neuronal histamine, in TMN, PVN, and VMH compared with the PBS group.
3. Change in the histamine and t-MH content with the central infusion of CRH and -hCRH
The central infusion of CRH did not affect the concentrations of histamine in the hypothalamic nuclei, with the exception of the TMN, where infusion elevated the histamine concentration compared with PBS infusion. However, the accumulation of t-MH was more accelerated after CRH infusion than after PBS infusion not only in the TMN, but also in the PVN and the VMH. Pretreatment with -hCRH suppressed the increase of histamine and t-MH by CRH infusion in the hypothalamus.
4. Immunohistochemical staining of histamine cell bodies for CRH type 1 receptor (CRH1-R) and CRH type 2 receptor (CRH2-R)
The histamine cell body CRH1-R as well as CRH2-R in the TMN were double-labeled immunohistochemically. CRH1-R was localized the histamine cell body. In contrast to the positive staining for CRH1-R, CRH2-R was not present on the histamine cell bodies.
5. Change in the t-MH and CRH content with a central infusion of leptin and exendin(9–39) or -hCRH
Central infusion of leptin increased CRH content in the TMN, PVN, and VMH compared with the PBS group. Pretreatment with exendin(9–39), a GLP-1 antagonist, attenuated these effects of leptin. Central infusion of leptin increased the pargyline-induced accumulation of t-MH in the TMN, PVN, and VMH compared with the PBS group. Pretreatment with exendin(9–39), -hCRH, or exendin(9–39) plus -hCRH attenuated the effects of leptin on t-MH (Fig. 2
). In the LH there were no significant differences in CRH and t-MH content among PBS, leptin, and leptin pretreated with each antagonist groups.
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CONCLUSIONS AND SIGNIFICANCE
GLP-1, CRH, and hypothalamic neuronal histamine act as anorexigenic substances in the hypothalamus under the control of leptin. However, their functional relationships, especially between GLP-1 and histamine, are still uncertain. The present study demonstrated that depletion of neuronal histamine by pretreatment with FMH partially attenuated the GLP-1-induced suppression of food intake. This indicates that endogenous neuronal histamine mediates the suppressive effect of GLP-1 on food intake. Therefore, it is important to analyze how GLP-1 affects hypothalamic neuronal histamine. The transmethylation of histamine into t-MH, a major metabolite of histamine, and its subsequent deamination provide the major metabolic pathway of histamine in the brain. Histamine released from a nerve terminal is rapidly converted into its metabolite, t-MH. Therefore, it is more informative to analyze histamine release by measuring its metabolite than to rely on a measurement of the brain histamine level itself. Pretreatment with pargyline, an inhibitor of monoamine oxidase B, is useful for this assessment as it induces the accumulation of t-MH in the extraneuronal space. We showed that a central infusion of GLP-1 increased the levels of both amines in the TMN, the origin of histamine neurons, but only t-MH level in the PVN and VMH, the sites histamine neurons project to. Therefore, we speculate that central infusion of GLP-1 increases histamine turnover, synthesis, and release in the PVN and VMH and that GLP-1 suppresses feeding in part via the activation of neuronal histamine.
No neuronal projections of GLP-1-containing neurons or localization of GLP-1 receptors were identified in the TMN, the site of histamine neuron cell bodies. A possible explanation is that GLP-1 influences histamine release from the nerve terminal at the projection site of histamine neurons. In fact, GLP-1 increased histamine turnover in the PVN and VMH. However, this is unlikely, because administration of GLP-1 affected histamine and t-MH content in the TMN. Rather, it is reasonable to postulate that GLP-1 affects neuronal histamine via the mediation of other GLP-1-responsive substance(s). Previous studies showed that central administration of GLP-1 increased corticosterone in rats and activated c-fos expression in CRH neurons in the PVN. Furthermore, GLP-1 neurons stimulate CRH neurons via the GLP-1 receptor (GLP-1-R). These results are consistent with our findings in which the central infusion of GLP-1 elevated the CRH content in the PVN. We also demonstrated that pretreatment with -hCRH, a CRH antagonist, completely attenuated GLP-1-induced suppression of food intake.
Our previous study demonstrated that central administration of CRH increased histamine turnover in the hypothalamus. Second, the CRH-induced increase in histamine turnover was suppressed by pretreatment with -hCRH in present study. Third, we identified the neurohistological expression of CRH1-R on histamine neuron cell bodies in the TMN. Therefore, we hypothesized that CRH mediates GLP-1 signaling to neuronal histamine. This hypothesis was supported by our finding that the GLP-1-induced increase in histamine turnover in each nucleus was attenuated by pretreatment with -hCRH.
GLP-1 is a potential target for leptin in the control of feeding behavior because the long isoform leptin receptor is localized to GLP-1 neurons. Acute administration of exendin(9–39) greatly attenuates leptin-induced reductions in food intake and body weight. Like GLP-1, both CRH and neuronal histamine are under the control of leptin. Next, we analyzed how the neuronal linkage from GLP-1 to neuronal histamine via CRH functions downstream in the leptin pathway. First, we found that pretreatment with exendin(9–39) attenuated the leptin-induced increase in the CRH content of the PVN, indicating that GLP-1 mediates leptin signaling to CRH neurons in the PVN. Second, the leptin-induced increase in the t-MH content was attenuated by pretreatment with exendin(9–39) in the TMN, PVN, and VMH. This indicates that GLP-1 mediates leptin signaling to neuronal histamine. Finally, the leptin-induced increase in histamine turnover was attenuated by pretreatment with -hCRH, indicating CRH as a mediator for leptin signaling to neuronal histamine. We therefore conclude there is a signaling cascade from leptin to GLP-1, CRH, and neuronal histamine.
Figure 3
shows our current model of the neuron network involving the signaling cascade from leptin to neuronal histamine. GLP-1 regulates histamine neurons in the TMN via GLP-1 receptors expressed on CRH neurons and histamine suppresses food intake via H1 receptors expressed on feeding-related neurons in the PVN and the VMH. Leptin stimulates histamine neurons via leptin receptors (Ob-Rs) expressed on GLP-1 and CRH neurons.
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FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-2384fje; doi: 10.1096/fj.04-2457fje
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  L. Huo, K. M. Gamber, H. J. Grill, and C. Bjorbaek Divergent Leptin Signaling in Proglucagon Neurons of the Nucleus of the Solitary Tract in Mice and Rats Endocrinology, February 1, 2008; 149(2): 492 - 497. [Abstract] [Full Text] [PDF]
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