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Rôles physiologiques du récepteur nucléaire aux lipides "Peroxisome proliferator-activated receptor O" (implication dans le syndrome métabolique)

Authors
Type
Thesis
Publication Date
Jun 14, 2003
Defense Date
Jan 15, 2003
Source
USPC - SET - SVS
Keywords
License
Unknown
External links

Abstract

Peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors which regulate fatty acid and carbohydrate metabolism. Among the three known members (PPARa,g,b/d), role of PPARd is not clearly established. We used a positive approach, by over-expressing the native receptor and a negative one, by expressing a dominant-negative form of PPARd : the E411P, to established the role of PPARd in various cellular contexts. In preadipose cells, PPARd is the mediator of fatty acid-controlled differentiation. PPARd mediates the effects of long chain fatty acid (LCFA) on post-confluent cell proliferation. In myoblast, PPARd mediates the inhibitory effects of LCFA on myogenesis, and acts as a key component in myoblast convertion into adipose-like cells. In myotubes, activation of PPARd leads to the induction of genes involved in lipid metabolism and results in an increase of fatty acid oxidation. The in vivo role of PPARd in muscle was assessed by developing a CRE/lox murine model of PPARd tissue-specific over-expression. Effects of this PPARd over-expression on muscle development and muscle oxidative capacity were then investigated regarding to nutritional status. Results showed that PPARd over-expression led to changes in muscle pattern of myofibers subtype and enzyme activities towards larger oxidative capacity as well as up-regulation of genes involved in fatty acid transport and catabolism. Moreover, we observed a reduction in white adipose mass resulting from a decrease in adipocyte size. These results strongly suggest a key role of PPARd in skeletal muscle metabolism and suggest that its activation could prevent lipid-associated disorders such as type 2 diabetes.

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