Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues

Nathan K. LeBrasseur, Meghan Kelly, Tsu Shuen Tsao, Stephen R. Farmer, Asish K. Saha, Neil B. Ruderman, Eva Tomas

Research output: Contribution to journalArticle

214 Scopus citations

Abstract

Thiazolidinediones (TZDs) are insulin-sensitizing agents used in the treatment of type 2 diabetes. A widely held view is that their action is secondary to transcriptional events that occur when TZDs bind to the nuclear receptor PPARγ in the adipocyte and stimulate adipogenesis. It has been proposed that this increases insulin sensitivity, at least in part, 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 also acutely activate AMPK in skeletal muscle and other tissues by a mechanism that is likely independent of PPARγ-regulated gene transcription. Thus incubation of isolated rat EDL muscles in medium containing 5 μM troglitazone for 15 min (too brief to be attributable to transcription) significantly increased pAMPK and pACC. At a concentration of 100 μM, troglitazone maximally increased these parameters and caused twofold increases in 2-deoxy-D-glucose uptake and the oxidation of exogenous [ 14C]palmitate. Time course studies revealed that troglitazone-induced increases in pAMPK and pACC abundance at 15 min were paralleled by an increase in the AMP-to-ATP ratio and that by 60 min all of these parameters had returned to baseline values. Increases in pAMPK and pACC were also observed in skeletal muscle, liver, and adipose tissue in intact rats 15 min 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 PPARγ 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 PPARγ-mediated gene transcription.

Original languageEnglish (US)
Pages (from-to)E175-E181
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume291
Issue number1
DOIs
StatePublished - Jul 17 2006

Keywords

  • Acetyl-coenzyme A carboxylase
  • Adiponectin
  • Diabetes
  • Insulin sensitivity
  • Metabolism

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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