AMPK activation by long chain fatty acyl analogs

Biochem Pharmacol. 2008 Nov 15;76(10):1263-75. doi: 10.1016/j.bcp.2008.08.028. Epub 2008 Sep 3.

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 beta-oxidized or esterified lipid products. Substituted alpha,omega-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 beta-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 (alpha(1)beta(1)gamma(1))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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • AMP-Activated Protein Kinases
  • Animals
  • Cell Line
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Fatty Acids / chemistry*
  • Fatty Acids / pharmacology*
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Multienzyme Complexes / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Fatty Acids
  • Multienzyme Complexes
  • Prkag1 protein, mouse
  • PRKAA1 protein, human
  • PRKAB1 protein, human
  • PRKAG1 protein, human
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases