Abstract
In the mouse hypothalamus, ciliary neurotrophic factor (CNTF) is mainly expressed by ependymal cells and tanycytes of the ependymal layer covering the third ventricle. Since exogenously administered CNTF causes reduced food intake and weight loss, we tested whether endogenous CNTF might be involved in energy balance regulation. We thus evaluated CNTF production and responsiveness in the hypothalamus of mice fed a high-fat diet (HFD), of ob/ob obese mice, and of mice fed a calorie restriction (CR) regimen. RT-PCR showed that CNTF mRNA increased significantly in HFD mice and decreased significantly in CR animals. Western blotting confirmed that CNTF expression was higher in HFD mice and reduced in CR mice, but high interindividual variability blunted the significance of these differences. By immunohistochemistry, hypothalamic tuberal and mammillary region tanycytes stained strongly for CNTF in HFD mice, whereas CR mice exhibited markedly reduced staining. RT-PCR and Western blotting disclosed that changes in CNTF expression were paralleled by changes in the expression of its specific receptor, CNTF receptor α (CNTFRα). Injection of recombinant CNTF and detection of phospho-signal transducer and activator of transcription 3 (P-STAT3) showed that CNTF responsiveness by the ependymal layer, mainly by tanycytes, was higher in HFD than CR mice. In addition, in HFD mice CNTF administration induced distinctive STAT3 signaling in a large neuron population located in the dorsomedial and ventromedial nuclei, perifornical area and mammillary body. The hypothalamic expression of CNTF and CNTFRα did not change in the hyperphagic, leptin-deficient ob/ob obese mice; accordingly, P-STAT3 immunoreactivity in CNTF-treated ob/ob mice was confined to ependymal layer and arcuate neurons. Collectively, these data suggest that hypothalamic CNTF is involved in controlling the energy balance and that CNTF signaling plays a role in HFD obese mice at specific sites.
Highlights
Ciliary neurotrophic factor (CNTF) is a 22 kDa cytokine belonging to the interleukin (IL)-6 family, a group of structurally related cytokines that include IL-11, oncostatin M, leukemia inhibitory factor (LIF), cardiotrophin-1, cardiotrophinlike cytokine and, more recently, neuropoietin (Bauer et al, 2007)
The increase appeared to be restricted to the hypothalamus, because no differences in CNTF expression were found in the samples containing the remaining brain portions
A significant increase of CNTFRα mRNA was found in the hypothalamus of high-fat diet (HFD) mice compared with controls (Figure 2C), whereas no differences in CNTFRα mRNA levels were detected in the extracts of the remaining brain portions
Summary
Ciliary neurotrophic factor (CNTF) is a 22 kDa cytokine belonging to the interleukin (IL)-6 family, a group of structurally related cytokines that include IL-11, oncostatin M, leukemia inhibitory factor (LIF), cardiotrophin-1, cardiotrophinlike cytokine and, more recently, neuropoietin (Bauer et al, 2007). In the peripheral nervous system, CNTF produced by Schwann cells is essential for the postnatal maintenance of motor neurons (Holtmann et al, 2005). Ablation of the mouse CNTF gene by homologous recombination leads to a progressive atrophy and loss of motor neurons that is more significant in older animals (Masu et al, 1993). Therapeutic trials where patients with the motor neuron disease amyotrophic lateral sclerosis were treated with human recombinant CNTF (ACTS, 1996; Miller et al, 1996) failed to provide satisfactory effects on motor performances and were associated with significant side effects, including anorexia and weight loss. Subsequent studies using Axokine, a modified form of human CNTF with improved potency and stability, www.frontiersin.org
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