AMPK activation by long chain fatty acyl analogs

Ghadeer Za'tara, Jacob Bar-Tana, Bella Kalderon, Marianne Suter, Etedal Morad, Dmitry Samovski, Dietbert Neumann, Rachel Hertz

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

The antidiabetic efficacy of first-line insulin sensitizers (e.g., metformin, glitazones) is accounted for by activation of AMP-activated protein kinase (AMPK). Long chain fatty acids (LCFA) activate AMPK, but their putative antidiabetic efficacy is masked by their β-oxidized or esterified lipid products. Substituted α,ω-dicarboxylic acids of 14-18 carbon atoms in length (MEDICA analogs) are not metabolized beyond their acyl-CoA thioesters, and may therefore simulate AMPK activation by LCFA while avoiding LCFA turnover into β-oxidized or esterified lipid products. MEDICA analogs are shown here to activate AMPK and some of its downstream targets in vivo, in cultured cells and in a cell-free system consisting of the (α1β1γ1)AMPK recombinant and LKB1-MO25-STRAD (AMPK-kinase) recombinant proteins. AMPK activation by MEDICA is accompanied by normalizing the hyperglycemia-hyperinsulinemia of diabetic db/db mice in vivo with suppression of hepatic glucose production in cultured liver cells. Activation of AMPK by MEDICA or LCFA is accounted for by (a) decreased intracellular ATP/AMP ratio and energy charge by the free acid, (b) activation of LKB1 phosphorylation of AMPK(Thr172) by the acyl-CoA thioester. The two activation modes are complementary since LKB1/AMPK activation by the CoA-thioester is fully evident under conditions of excess AMP. MEDICA analogs may expand the arsenal of AMPK activators used for treating diabetes type 2.

Original languageEnglish
Pages (from-to)1263-1275
Number of pages13
JournalBiochemical Pharmacology
Volume76
Issue number10
DOIs
StatePublished - Nov 15 2008

Keywords

  • AMPK
  • Acyl-CoA
  • Diabetes
  • Fatty acids
  • MEDICA

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