Fant X.,French National Center for Scientific Research |
Durieu E.,French National Center for Scientific Research |
Chicanne G.,Institute des Maladies Metaboliques et Cardiovasculaires I2MC |
Payrastre B.,Institute des Maladies Metaboliques et Cardiovasculaires I2MC |
And 6 more authors.
Molecular Pharmacology | Year: 2014
Leucettines, a family of pharmacological inhibitors of dualspecificity tyrosine phosphorylation regulated kinases and cdclike kinases (CLKs), are currently under investigation for their potential therapeutic application to Down syndrome and Alzheimer's disease. We here report that leucettine L41 triggers bona fide autophagy in osteosarcoma U-2 OS cells and immortalized mouse hippocampal HT22 cells, characterized by microtubuleassociated protein light chain 3 membrane translocation and foci formation. Leucettine L41-triggered autophagy requires the Unc-51-like kinase and is sensitive to the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and 3-methyladenine, suggesting that it acts through the mammalian target of rapamycin (mTOR)/PI3K-dependent pathway. Leucettine L41 does not act by modifying the autophagic flux of vesicles. Leucettine L41-induced autophagy correlates best with inhibition of CLKs. Leucettine L41 modestly inhibited phosphatidylinositol- 3-phosphate 5-kinase, FYVE domain-containing activity as tested both in vitro and in vivo, which may also contribute to autophagy induction. Altogether these results demonstrate that leucettines can activate the autophagic mTOR/PI3K pathway, a characteristic that may turn advantageous in the context of Alzheimer's disease treatment. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics. Source
Blasco-Baque V.,French Institute of Health and Medical Research |
Blasco-Baque V.,Institute des Maladies Metaboliques et Cardiovasculaires I2MC |
Blasco-Baque V.,University Paul Sabatier |
Blasco-Baque V.,Technical platform of Research in Odontology |
And 38 more authors.
Gut | Year: 2016
Objective To identify a causal mechanism responsible for the enhancement of insulin resistance and hyperglycaemia following periodontitis in mice fed a fat-enriched diet. Design We set-up a unique animal model of periodontitis in C57Bl/6 female mice by infecting the periodontal tissue with specific and alive pathogens like Porphyromonas gingivalis (Pg), Fusobacterium nucleatum and Prevotella intermedia. The mice were then fed with a diabetogenic/non-obesogenic fat-enriched diet for up to 3 months. Alveolar bone loss, periodontal microbiota dysbiosis and features of glucose metabolism were quantified. Eventually, adoptive transfer of cervical (regional) and systemic immune cells was performed to demonstrate the causal role of the cervical immune system. Results Periodontitis induced a periodontal microbiota dysbiosis without mainly affecting gut microbiota. The disease concomitantly impacted on the regional and systemic immune response impairing glucose metabolism. The transfer of cervical lymph-node cells from infected mice to naive recipients guarded against periodontitis-aggravated metabolic disease. A treatment with inactivated Pg prior to the periodontal infection induced specific antibodies against Pg and protected the mouse from periodontitis-induced dysmetabolism. Finally, a 1-month subcutaneous chronic infusion of low rates of lipopolysaccharides from Pg mimicked the impact of periodontitis on immune and metabolic parameters. Conclusions We identified that insulin resistance in the high-fat fed mouse is enhanced by pathogen-induced periodontitis. This is caused by an adaptive immune response specifically directed against pathogens and associated with a periodontal dysbiosis. © 2016 BMJ Publishing Group Ltd & British Society of Gastroenterology. Source
Boulet N.,University Paul Sabatier |
Boulet N.,Institute des Maladies Metaboliques et Cardiovasculaires I2MC |
Esteve D.,University Paul Sabatier |
Esteve D.,Institute des Maladies Metaboliques et Cardiovasculaires I2MC |
And 4 more authors.
Journal of Physiology and Biochemistry | Year: 2013
Human abdominal adipose tissue (AAT) can be divided into two compartments according to anatomical location to dermis layer, i.e. superficial and deep compartments (sAAT and dAAT). In morbidly obese patients, dAAT mass has been linked to obesity-associated pathologies. In the present study, we characterized in overweight healthy individuals human sAAT and dAAT cellular composition and adipogenic potential. Twelve paired sAAT and dAAT samples were collected. sAAT compared to dAATadipocytes are larger. In agreement with increased size, real-time PCR analyses performed on isolated adipocytes showed that sAAT adipocytes exhibited higher leptin transcript levels but also higher expression of genes involved in metabolism including hormone-sensitive lipase compared to dAAT adipocytes. Flow cytometry analyses performed on stroma-vascular fraction (SVF) showed no difference in the numbers of progenitor cells, endothelial cells and macrophages between sAAT and dAAT. Macrophage phenotypes were not distinct between both AAT compartments. However, CD3+ T lymphocyte number was higher in dAAT than in sAAT. Adipogenic potential of dAAT SVF was lower than sAAT SVF whereas the one of isolated progenitor cells was not distinct whatever the AAT compartments. Therefore, in overweight patients, both sAAT and dAAT compartments exhibit differences in terms of adipocytes and T lymphocyte accumulation. dAAT is characterized by higher T lymphocyte accumulation together with smaller less metabolically active adipocytes. The lower adipogenic potential of dAAT SVF is not due to intrinsic progenitor cell properties but more likely to the increased T lymphocyte accumulation. © University of Navarra 2012. Source