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Acute inhibition of central c-Jun N-terminal kinase restores hypothalamic insulin signalling and alleviates glucose intolerance in diabetic mice.
MedLine Citation:
PMID:  23301857     Owner:  NLM     Status:  Publisher    
The hypothalamus has been identified to be a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c- Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance since neuronal JNK-1 ablation in the mouse prevented high fat diet-induced obesity (DIO) and increased energy expenditure as well as insulin sensitivity. Here we investigated whether central JNK inhibition is associated with sensitization of hypothalamic insulin signalling in mice fed a high fat diet for three weeks and in leptin-deficient mice. We determined whether intracerebroventricular (ICV) injection of a pharmacological JNK inhibitor (SP600125) improves impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the ARC and the VMH in both mouse models, relative to normo-glycemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute ICV injection of SP600125 ameliorates glucose tolerance within 30 minutes in both leptin-deficient and DIO mice. Given the acute nature of ICV injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is regarded to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-AKT (Ser473) and phospho-GSK-3β (Ser9), which are important markers of insulin signalling. Collectively our data suggest that acute inhibition of central JNK improves impaired glucose homeostasis and is associated with sensitization of hypothalamic insulin signalling. © 2013 British Society for Neuroendocrinology.
Jonas Benzler; Goutham K Ganjam; Karen Legler; Sigrid Stöhrz; Manon Krüger; Juliane Steger; Alexander Tups
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-10
Journal Detail:
Title:  Journal of neuroendocrinology     Volume:  -     ISSN:  1365-2826     ISO Abbreviation:  J. Neuroendocrinol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8913461     Medline TA:  J Neuroendocrinol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 British Society for Neuroendocrinology.
Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Marburg, Germany.
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