Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Ergebnis 9 von 514

Details

Autor(en) / Beteiligte
Titel
Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin
Ist Teil von
  • Nature medicine, 2013-12, Vol.19 (12), p.1649-1654
Ort / Verlag
New York: Nature Publishing Group US
Erscheinungsjahr
2013
Quelle
MEDLINE
Beschreibungen/Notizen
  • Metformin is one of the most widely prescribed therapeutics for type 2 diabetes. But exactly how it works is still unclear. Gregory Steinberg and colleagues now show that it does so by activation of the enzyme AMP-activated protein kinase (Ampk) and Ampk's obligate targeting of two key enzymes involved in lipid homeostasis. The obesity epidemic has led to an increased incidence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. AMP-activated protein kinase (Ampk) regulates energy homeostasis and is activated by cellular stress, hormones and the widely prescribed type 2 diabetes drug metformin 1 , 2 . Ampk phosphorylates mouse acetyl-CoA carboxylase 1 (Acc1; refs. 3 , 4 ) at Ser79 and Acc2 at Ser212, inhibiting the conversion of acetyl-CoA to malonyl-CoA. The latter metabolite is a precursor in fatty acid synthesis 5 and an allosteric inhibitor of fatty acid transport into mitochondria for oxidation 6 . To test the physiological impact of these phosphorylation events, we generated mice with alanine knock-in mutations in both Acc1 (at Ser79) and Acc2 (at Ser212) (Acc double knock-in, AccDKI). Compared to wild-type mice, these mice have elevated lipogenesis and lower fatty acid oxidation, which contribute to the progression of insulin resistance, glucose intolerance and NAFLD, but not obesity. Notably, AccDKI mice made obese by high-fat feeding are refractory to the lipid-lowering and insulin-sensitizing effects of metformin. These findings establish that inhibitory phosphorylation of Acc by Ampk is essential for the control of lipid metabolism and, in the setting of obesity, for metformin-induced improvements in insulin action.

Weiterführende Literatur

Empfehlungen zum selben Thema automatisch vorgeschlagen von bX