Abstract
Ciliary neurotrophic factor (CNTF) induces weight loss in obese rodents and humans through activation of the hypothalamic Jak-STAT (Janus kinase-signal transducer and activator of transcription) signaling pathway. Here, we tested the hypothesis that CNTF also affects the brainstem centers involved in feeding and energy balance regulation. To this end, wild-type and leptin-deficient (ob/ob and db/db) obese mice were acutely treated with intraperitoneal recombinant CNTF. Coronal brainstem sections were processed for immunohistochemical detection of STAT3, STAT1, STAT5 phosphorylation and c-Fos. In wild-type mice, CNTF treatment for 45 min induced STAT3, STAT1, and STAT5 phosphorylation in neurons as well as glial cells of the area postrema; here, the majority of CNTF-responsive cells activated multiple STAT isoforms, and a significant proportion of CNTF-responsive glial cells bore the immaturity and plasticity markers nestin and vimentin. After 120 min CNTF treatment, c-Fos expression was intense in glial cells and weak in neurons of the area postrema, it was intense in several neurons of the rostral and caudal solitary tract nucleus (NTS), and weak in some cholinergic neurons of the dorsal motor nucleus of the vagus. In the ob/ob and db/db mice, Jak-STAT activation and c-Fos expression were similar to those induced in wild-type mouse brainstem. Treatment with CNTF (120 min, to induce c-Fos expression) and leptin (25 min, to induce STAT3 phosphorylation) demonstrated the co-localization of the two transcription factors in a small neuron population in the caudal NTS portion. Finally, weak immunohistochemical CNTF staining, detected in funiculus separans, and meningeal glial cells, matched the modest amount of CNTF found by RT-qPCR in micropunched area postrema tissue, which in contrast exhibited a very high amount of CNTF receptor. Collectively, the present findings show that the area postrema and the NTS exhibit high, distinctive responsiveness to circulating exogenous and, probably, endogenous CNTF.
Highlights
Ciliary neurotrophic factor (CNTF), originally isolated from chick embryo ciliary ganglion, was first characterized for its action on parasympathetic cholinergic neurons (Adler et al, 1979; Skaper et al, 1984)
To assess whether circulating CNTF exerts a direct, specific effect on the mouse brainstem, coronal slices from mice treated with an intraperitoneal injection of vehicle or recombinant CNTF for 45 min were processed for immunohistochemical P-STAT detection
Double-staining experiments, performed at different rostrocaudal levels, showed that P-STAT3 staining was ubiquitous and was detected in the funiculus separans, the glial structure on the ventrolateral border of the area postrema separating it from the adjacent nuclei (McKinley et al, 2003), whereas immunoreactivity for P-STAT1 and, especially, P-STAT5 involved a smaller number of cells, most of which were located in the central portion of the area postrema (Figures 1D–F)
Summary
Ciliary neurotrophic factor (CNTF), originally isolated from chick embryo ciliary ganglion, was first characterized for its action on parasympathetic cholinergic neurons (Adler et al, 1979; Skaper et al, 1984). It exerts important effects on neuronal and glial precursors during the development of the central (CNS) and peripheral nervous system, and on the postnatal maintenance of sensory, sympathetic, and motor neurons (Sendtner et al, 1994; Sleeman et al, 2000). The substantial weight loss seen in these patients after systemic CNTF administration unveiled a role for it in human body metabolism and energy balance regulation. The mechanisms by which exogenous CNTF regulates the energy balance are thought to involve both hypothalamic centers, where it promotes satiety, and peripheral organs, including muscle, liver, and adipose tissue, where it increases insulin sensitivity and energy expenditure (Matthews and Febbraio, 2008; Pasquin et al, 2015)
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