Short communicationSuppressor of cytokine signaling 3 in the human hypothalamus☆
Introduction
The hypothalamus senses hormonal and nutrient signals from the circulation and responds by regulating food-intake and metabolism in order to maintain energy homeostasis. Hypothalamic leptin signaling plays a pivotal role in this homeostatic regulation [4], [7], [10], [12], [18], [20]. Data on hypothalamic leptin signaling are almost exclusively from rodent studies, whereas very little is known about leptin signaling in the human hypothalamus. In rodents, leptin increases the expression of the anorexigenic neuropeptide α-melanocyte stimulating hormone (αMSH) in the arcuate nucleus (ARC) [19]. In addition, leptin decreases the expression of the orexigenic peptides neuropeptide Y (NPY) and agouti regulated protein (AgRP) in the ARC [7], [22], [23], [24]. Leptin acts on the hypothalamus via activation of the phosphatidylinositol-3 kinase signaling pathway [17], and induces suppressor-of-cytokine-signaling (SOCS)-3 mRNA in the hypothalamus [5]. SOCS3 in turn inhibits the leptin receptor-mediated signal transduction serving as an internal negative feedback mechanism [5]. The distribution of SOCS3 in the human hypothalamus and the possible relationship between SOCS3 expression and serum leptin are currently unknown.
Our group has previously described a series of patients of whom both hypothalamic tissue samples and a serum sample taken within 24 h before death was available for research purposes. This unique combination allowed us to investigate the relationship between serum leptin concentrations and NPY mRNA expression in the infundibular nucleus (IFN) of the hypothalamus, which is the human equivalent of the ARC [9]. Leptin levels and NPY mRNA were negatively correlated in these patients. In addition, we observed higher serum leptin levels in patients with more severe illness [9]. Therefore, we concluded that decreased NPY expression in the IFN may be one of the determinants of the anorexia occurring in severely ill patients, in line with increased serum leptin levels reported by other investigators in the context of severe illness [6].
The importance to further investigate leptin signaling pathways in the human hypothalamus is stressed by a recent study by Menyhert et al. [14], who showed that, in contrast to rodent hypothalamus, in human hypothalamus CART and αMSH are not colocalized indicating the presence of interspecies differences in neuronal populations involved in feeding regulation. Thus, the aim of the present study was to reinvestigate the unique post-mortem hypothalami published earlier study the expression of αMSH, AgRP, NPY and SOCS3 expression in the human IFN and PVN, and to investigate the relationship between these neuropeptide expressions and serum leptin in a blood sample taken just before death.
Section snippets
Subjects
We studied post-mortem hypothalamus specimens obtained from 9 subjects in whom serum leptin levels (not determined in 2 subjects) were determined in a blood sample taken within 24 h before death. Histological treatment, clinicopathological data and serum thyroid hormone and leptin concentrations of these patients have been published previously [8], [9]. Brain material was obtained from The Netherlands Brain Bank at The Netherlands Institute for Neuroscience (Director Dr. I. Huitinga) in
Results
We performed quantification of AgRP immunostaining in the IFN in subjects in whom we had previously quantified NPY immunoreactivity [9]. Total NPY immunoreactivity and AgRP immunoreactivity in the IFN showed a statistically significant correlation (r = 0.80, p = 0.01), in line with results from rodent studies. The correlation between total AgRP immunoreactivity in the IFN and TRH mRNA expression in the PVN reached borderline significance (r = 0.67, p = 0.05). No correlation between αMSH
Discussion
In the present study, we report for the first time the hypothalamic distribution of SOCS3 in the human hypothalamus. The neuronal distribution of SOCS3 in the human hypothalamus appears to be in general agreement with that in rodents, although the relative expression levels between the hypothalamic nuclei differ between species. In rodents high SOCS3 expression is observed in the ARC after leptin stimulation [5]. We only found very low expression levels in the IFN. Since the subjects studied
Acknowledgments
This work was supported by a Veni-grant of The Netherlands Organization for Health Research and Development, and the Dutch Diabetes Foundation. The authors would like to thank B. Fisser, J. Anink and J. van Heerikhuize for excellent technical assistance.
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This work was supported by a Veni-grant of The Netherlands Organization for Health Research and Development, and the Dutch Diabetes Foundation.