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Pyruvate dehydrogenase kinase 4: regulation by thiazolidinediones and implication in glyceroneogenesis in adipose tissue

Thomas Cadoudal, Emilie Distel, Sylvie Durant, Françoise Fouque, Jean-Marc Blouin, Martine Collinet, Sylvie Bortoli, Claude Forest, and Chantal Benelli

INSERM UMR-S 747 ; Université Paris Descartes, Centre Universitaire des Saints-Pères, 45 rue des Saints-Pères, F-75006, Paris, France

OBJECTIVE: Pyruvate dehydrogenase complex (PDC) serves as metabolic switch between glucose and fatty acid utilisation. PDC activity is inhibited by PDC kinase (PDK). PDC shares the same substrate, i.e pyruvate, as glyceroneogenesis, a pathway controling fatty acid release from white adipose tissue (WAT). Thiazolidinediones activate glyceroneogenesis. We studied the regulation by rosiglitazone (RSG) of PDK2 and PDK4 isoforms and tested the hypothesis that glyceroneogenesis could be controlled by PDK.

RESEARCH DESIGN AND METHODS: RSG was administered to Zucker fa/fa rats then PDK4 and PDK2 mRNA were examined in subcutaneous, periepididymal and retroperitoneal WAT, liver and muscle by real-time RT-PCR. Cultured WAT explants from humans and rats and 3T3-F442A adipocytes were RSG-treated before analyses of PDK2 and PDK4 mRNA and protein. siRNA was transfected by electroporation. Glyceroneogenesis was determined using [1-¹⁴C]-pyruvate incorporation into lipids.

RESULTS: RSG increased PDK4 mRNA in all WAT depots but not in liver and muscle. PDK2 transcript was not affected. This isoform selectivity was also found in ex vivo-treated explants. In 3T3-F442A adipocytes, PDK4 gene expression was strongly and selectively induced by RSG in a direct and transcriptional manner, with a concentration required for half-maximum effect at 1nM. The use of dichloroacetic acid (DCA) or leelamine, two PDK inhibitors, or a specific PDK4 siRNA demonstrated that PDK4 participated in glyceroneogenesis, therefore altering non esterified fatty acid (NEFA) release in both basal and RSG-activated conditions.

CONCLUSIONS: These data show that PDK4 upregulation in adipocytes participates in the hypolipidemic effect of thiazolidinediones through modulation of glyceroneogenesis.

Key Words: Adipose tissue • glyceroneogenesis • thiazolidinediones • pyruvate dehydrogenase kinase • phosphoenolpyruvate carboxykinase

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