Jortay J.,Unite dEndocrinologie et Metabolisme |
Senou M.,Catholic University of Leuven |
Delaigle A.,Unite dEndocrinologie et Metabolisme |
Noel L.,Unite dEndocrinologie et Metabolisme |
And 4 more authors.
Endocrinology | Year: 2010
Adiponectin (ApN) exhibits metabolic and antiinflammatory properties. This hormone is exclusively secreted by adipocytes under normal conditions. We have shown that ApN was induced in tibialis anterior muscle of mice injected with lipopolysaccharide (LPS) and in C2C12 myotubes cultured with proinflammatory cytokines. We hypothesized that muscle ApN could be a local protective mechanism to counteract excessive inflammatory reaction and oxidative damage. To test this paradigm, we examined whether muscles of ApN-knockout (KO) mice exhibit a higher degree of oxidative stress and apoptosis than wild-type mice when challenged by ip LPS and whether these abnormalities may be corrected by local administration of ApN. Eventually we investigated the effects of ApN in vitro. When compared with wild-type mice, ApN-KO mice exhibited myocyte degenerescence, especially after LPS. Myocytes of ApN-KO mice also displayed much stronger immunolabeling for markers of oxidative stress (peroxiredoxin-3/5 and heme oxygenase-1) as well as for a lipid peroxidation product (hydroxynonenal). Expression of TNF-α, caspase-6, a marker of apoptosis, and nuclear factor-κB was enhanced as well. Eventually muscle electrotransfer of the ApN gene, which did not induce any rise of systemic ApN, corrected all these abnormalities in LPS-injected ApN-KO mice. Likewise, ApN attenuated LPS-induced production of proinflammatory cytokines and activation of nuclear factor-κB in C2C12 cells. Thus, induction of ApN into skeletal muscle in response to an inflammatory aggression appears to be a crucial mechanism to counteract in an autocrine or paracrine fashion excessive inflammatory damage, oxidative stress, and subsequent apoptosis. Copyright © 2010 by The Endocrine Society.
Dubois E.,Free University of Colombia |
Jacoby M.,Free University of Colombia |
Blockmans M.,Free University of Colombia |
Pernot E.,Free University of Colombia |
And 7 more authors.
Cellular Signalling | Year: 2012
The function of the phosphoinositide 5-phosphatase Ship2 was investigated in a new mouse model expressing a germline catalytically-inactive Ship2Δ/Δ mutant protein. Ship2Δ/Δ mice were viable with defects in somatic growth and in development of muscle, adipose tissue and female genital tract. Lipid metabolism and insulin secretion were also affected in these mice, but glucose tolerance, insulin sensitivity and insulin-induced PKB phosphorylation were not. We expected that the expression of the catalytically inactive Ship2 protein in PI 3'-kinase-defective p110αD933A/+ mice would counterbalance the phenotypes of parental mice by restoring normal PKB signaling but, for most of the parameters tested, this was not the case. Indeed, often, the Ship2Δ/Δ phenotype had a dominant effect over the p110αD933A/+ phenotype and, sometimes, there was a surprising additive effect of both mutations. p110αD933A/+Ship2Δ/Δ mice still displayed a reduced PKB phosphorylation in response to insulin, compared to wild type mice yet had a normal glucose tolerance and insulin sensitivity, like the Ship2Δ/Δ mice. Together, our results suggest that the Ship2Δ/Δ phenotype is not dependent on an overstimulated class I PI 3-kinase-PKB signaling pathway and thus, indirectly, that it may be more dependent on the lack of Ship2-produced phosphatidylinositol 3,4-bisphosphate and derived phosphoinositides. © 2012 Elsevier Inc.