Muscle-specific interleukin-6 deletion influences body weight and body fat in a sex-dependent manner.

Interleukin-6 (IL-6) is a major cytokine controlling not only the immune system but also basic physiological variables such as body weight and metabolism. While central IL-6 is clearly implicated in the latter, the putative role of peripheral IL-6 controlling body weight remains unclear. We herewith report results obtained in muscle-specific IL-6 KO (mIL-6 KO) mice. mIL-6 KO male mice fed a high-fat diet (HFD, 58.4% kcal from fat) or a control diet (18%) gained less weight and body fat than littermate floxed male mice, while the opposite pattern was observed in female mice. Food intake was not affected by muscle IL-6 deficiency, but male and female mIL-6 KO mice were more and less active, respectively, in the hole-board test. Moreover, female mIL-6 KO mice did not control adequately their body temperature upon exposure to 4°C, suggesting a role of muscle IL-6 in energy expenditure. At least part of this regulatory role of muscle IL-6 may be mediated by the hypothalamus, as IL-6 deficiency regulated the expression of critical hypothalamic neuropeptides (NPY, AgRP, POMC, CRH and preproOX). Leptin and insulin changes cannot explain the phenotype of these mice. In summary, the present results demonstrate that muscle IL-6 controls body weight and body fat in a sex-specific fashion, influencing the expression of the main neuropeptides involved in energy homeostasis.

Resistance of neonatal primary astrocytes against Fas-induced apoptosis depends on silencing of caspase 8.

In the present report, we have found that primary fetal astrocytes express caspase 8 and undergo apoptosis in response to Fas ligation. In contrast, neonatal astrocytes do not express detectable levels of the enzyme and are resistant to Fas killing. Fas-induced apoptosis can be restored in these cells by up-regulation of caspase 8 expression by means of transient transfection with a caspase 8-encoding plasmid. Furthermore, treatment of primary astrocytes with the demethylating agent 5-Aza-dC restores caspase 8 expression and increases the sensibility of neonatal astrocytes to the cytotoxic effect of Fas activation. Altogether, our findings indicate that silencing of caspase 8 gene is a key factor controlling the outcome of neonatal astrocytes upon Fas engagement.

Bimodal effect of interferon-ß on astrocyte proliferation and survival: Importance of nuclear factor-κB.

Accumulating evidence indicates that interferon-ß (IFN-ß) can modify the complex immunopathogenic scenario causing clinical relapse activity and disease progression in MS. However, the beneficial effects of IFN-ß in MS patients may also depend on non-immune mechanisms, including the modulation of astrocyte function. In the present report, we have shown that, depending on the dose, IFN-ß treatment can either promote astrocyte proliferation and survival, or result astrocyte death. These actions depend, at least in part, on the regulation of nuclear factor-kappa B (NF-κB), an inducible transcription factor present in neurons and glia. This bimodal effect of IFN-ß adds a new layer of complexity in the actions of IFN-ß within the CNS.

Interferon-beta protects astrocytes against tumour necrosis factor-induced apoptosis via activation of p38 mitogen-activated protein kinase.

Several large clinical trials have demonstrated that interferon-beta (IFN-beta) therapy is effective in the treatment of multiple sclerosis (MS) patients. However, the mechanisms underlying the beneficial effects of IFN-beta are not fully understood. Most of the effort in the study of the relevant mechanisms of IFN-beta has dealt with its immunomodulatory actions. However, the beneficial effects of IFN-beta in MS patients may also depend on non-immune mechanisms, including the modulation of astrocyte function. In the present work, we have found that IFN-beta treatment protects astrocytes against tumour necrosis factor-induced apoptosis via activation of p38 mitogen-activated protein kinase. We propose that this effect may be of importance to protect astrocytes against apoptosis within the demyelinated plaques of the MS.

Thyroid status regulates CART but not AgRP mRNA levels in the rat hypothalamus.

We examined the effects of thyroid status on cocaine- and amphetamine-regulated transcript and agouti-related peptide expression in the rat hypothalamus. Hypo- and hyperthyroidism were induced in adult male rats, and the mRNA content of cocaine- and amphetamine-regulated transcript and agouti-related peptide was determined using in situ hybridization. Hyperthyroidism induces a reduction in cocaine- and amphetamine-regulated transcript mRNA levels in the paraventricular nucleus, without any change in the arcuate and dorsomedial nuclei and in the lateral hypothalamic area. On the other hand, hypothyroidism had not effect on cocaine- and amphetamine-regulated transcript expression in any of these nuclei. Agouti-related peptide expression in the arcuate nucleus was not affected by the thyroid status. These data indicate that the increments in food intake in hyperthyroidism could be mediated, at least in some extent, by a decreased expression, at the paraventricular nucleus of the hypothalamus, of the anorexigenic cocaine- and amphetamine-regulated transcript peptides.