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1 Diabetes and Metabolism Unit, Boston University School of Medicine, Boston, MA, USA
2 Whitehead Institute for Biomedical Research, Cambridge, MA, USA
3 Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: nrude{at}bumc.bu.edu.
Thiazolidinediones (TZDs) are insulin sensitizing agents used in the treatment of Type 2 Diabetes Mellitus and other disorders associated with insulin resistance. A widely held view is that their action is secondary to transcriptional events that occur when TZDs bind to the nuclear receptor PPAR
in the adipocyte, and stimulate adipogenesis. It has been proposed that this increases insulin sensitivity by enhancing lipid storage in adipose tissue leading to a decrease in plasma FFA and by increasing the expression and release of adiponectin, an adipokine that activates the fuel sensing enzyme AMP-activated protein kinase (AMPK). In this study, we report that TZDs acutely activate AMPK in skeletal muscle and other tissues and that they do so by a mechanism that is likely independent of PPAR-regulated gene transcription. Thus, incubation of isolated rat EDL muscles in media containing 5µM troglitazone for 15 minutes (too brief to be attributable to transcription) significantly increased the phosphorylation of AMPK (pAMPK) and ACC (pACC). At a concentration of 100µM, troglitazone maximally increased these parameters and caused 2-fold increases in 2-deoxyglucose uptake and the oxidation of exogenous 14C palmitate. Time course studies revealed that troglitazone-induced increases in pAMPK and pACC abundance at 15 minutes were paralleled by an increase in the AMP: ATP ratio, and that by 60 minutes all of these parameters had returned to baseline values. Increases in pAMPK and pACC were also observed in skeletal muscle, liver and adipose tissue of the intact rat 15 minutes after the administration of a single dose of troglitazone (10 mg/kg, IP). Likewise, troglitazone and another TZD, pioglitazone, caused rapid increases in pAMPK and pACC of equal magnitude in Swiss 3T3 fibroblasts with and without sufficient PPAR to mediate the expression of target genes. The results indicate that TZDs can act within minutes to activate AMPK in mammalian tissues. They suggest that this effect is associated with a change in cellular energy state and that it is not dependent on PPAR-mediated gene transcription.
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