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Gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor.

ABSTRACT: Ciliary neurotrophic factor (CNTF) exerts anorectic effects by overcoming leptin resistance via activation of hypothalamic neurons. However, the exact site of CNTF action in the hypothalamus has not yet been identified. Using Cre-loxP-mediated recombination in vivo, we have selectively ablated the common cytokine signaling chain gp130, which is required for functional CNTF signaling, in proopiomelanocortin (POMC)-expressing neurons. POMC-specific gp130 knockout mice exhibit unaltered numbers of POMC cells and normal energy homeostasis under standard and high fat diet. Endotoxin (LPS) and stress-induced anorexia and adrenocorticotropin regulation were unaffected in these animals. Strikingly, the anorectic effect of centrally administered CNTF was abolished in POMC-specific gp130 knockout mice. Correspondingly, in these animals, CNTF failed to activate STAT3 phosphorylation in POMC neurons and to induce c-Fos expression in the paraventricular nucleus. These data reveal POMC neurons as a critical site of CNTF action in mediating its anorectic effect.

SUBMITTER: Janoschek R

PROVIDER: S-EPMC1502296 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor.

Janoschek Ruth R Plum Leona L Koch Linda L Münzberg Heike H Diano Sabrina S Shanabrough Marya M Müller Werner W Horvath Tamas L TL Brüning Jens C JC

Proceedings of the National Academy of Sciences of the United States of America 20060703 28

Ciliary neurotrophic factor (CNTF) exerts anorectic effects by overcoming leptin resistance via activation of hypothalamic neurons. However, the exact site of CNTF action in the hypothalamus has not yet been identified. Using Cre-loxP-mediated recombination in vivo, we have selectively ablated the common cytokine signaling chain gp130, which is required for functional CNTF signaling, in proopiomelanocortin (POMC)-expressing neurons. POMC-specific gp130 knockout mice exhibit unaltered numbers of ...[more]

PMID: 16818888

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Project description:Macrophage migration inhibitory factor (MIF) is a chemokine that plays an essential role in immune system function. Previous studies suggested that MIF protects neurons in ischemic conditions. However, few studies are reported on the role of MIF in neurological recovery after ischemic stroke. The purpose of this study is to identify the molecular mechanism of neuroprotection mediated by MIF. Human neuroblastoma cells were incubated in Dulbecco's modified Eagle's medium under oxygen-glucose deprivation (OGD) for 4 hours and then returned to normal aerobic environment for reperfusion (OGD/R). 30 ng/mL MIF recombinant (30 ng/mL) or ISO-1 (MIF antagonist; 50 ?M) was administered to human neuroblastoma cells. Then cell cultures were assigned to one of four groups: control, OGD/R, OGD/R with MIF, OGD/R with ISO-1. Cell viability was analyzed using WST-1 assay. Expression levels of brain-derived neurotrophic factor (BDNF), microtubule-associated protein 2 (MAP2), Caspase-3, Bcl2, and Bax were detected by western blot assay and immunocytochemistry in each group to measure apoptotic activity. WST-1 assay results revealed that compared to the OGD/R group, cell survival rate was significantly higher in the OGD/R with MIF group and lower in the OGD/R with ISO-1 group. Western blot assay and immunocytochemistry results revealed that expression levels of BDNF, Bcl2, and MAP2 were significantly higher, and expression levels of Caspase-3 and Bax were significantly lower in the MIF group than in the OGD/R group. Expression levels of BDNF, Bcl2, and MAP2 were significantly lower, and expression levels of Caspase-3 and Bax were significantly higher in the ISO-1 group than in the OGD/R group. MIF administration promoted neuronal cell survival and induced high expression levels of BDNF, MAP2, and Bcl2 (anti-apoptosis) and low expression levels of Caspase-3 and Bax (pro-apoptosis) in an OGD/R model. These results suggest that MIF administration is effective for inducing expression of BDNF and leads to neuroprotection of neuronal cells against hypoxic injury.

Project description:Administration of ciliary neurotrophic factor (CNTF) to experimental animals exerts anti-obesity effects by acting on multiple targets. In white adipose tissue CNTF reduces lipid content, promotes fatty acid (FA) oxidation and improves insulin sensitivity. This study was performed to establish whether CNTF exerts similar effects on human white adipocytes. To this end, adipose differentiation was induced in vitro in human multipotent adipose-derived stem (hMADS) cells. CNTF receptor α (CNTFRα) expression was assessed in hMADS cells and adipocytes by qRT-PCR, Western blotting, and immunocytochemistry. After administration of human recombinant CNTF, signaling pathways and gene expression were evaluated by Western blotting and qRT-PCR. Glucose uptake was assessed by measuring 2-nitrobenzodeoxyglucose uptake with a fluorescence plate reader. Lastly, CNTF-induced anti-inflammatory responses were evaluated in hMADS adipocytes stressed with tumor necrosis factor α (TNFα) for 24 h. Results showed that CNTFRα protein expression was higher in undifferentiated hMADS cells than in hMADS adipocytes, where it was however clearly detectable. In hMADS adipocytes, 1 nM CNTF strongly activated the JAK-STAT3 (Janus kinase-signaling transducer and activator of transcription 3) pathway and acutely and transiently activated the AMPK (AMP-activated protein kinase) and AKT (protein kinase B) pathways. Acute CNTF treatment for 20 min significantly increased basal glucose uptake and was associated with increased AKT phosphorylation. Longer-term (24 and 48 h) treatment reduced the expression of lipogenic markers (FA synthase and sterol regulatory element-binding protein-1) and increased the expression of lipolytic [hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL)] and mitochondrial (peroxisome proliferator-activated receptor γ coactivator-1α and carnitine palmitoyltransferase 1) markers. In TNFα-treated hMADS adipocytes, CNTF significantly reduced the expression of monocyte chemoattractant protein 1 and TNFα-induced AKT inhibition. Collectively, these findings demonstrate for the first time that CNTF plays a role also in human adipocytes, driving their metabolism toward a less lipid-storing and more energy-consuming phenotype.

Dataset Information

Gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor.

Publications

gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor.

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