title: AMPK activation by long chain fatty acyl analogs.
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.
authors.affiliation: Department of Human Nutrition and Metabolism, Hebrew University Medical School, Ein Kerem, Jerusalem 91120, Israel.
authors.forename: Ghadeer
authors.initials: G
authors.lastname: Za'tara
authors.forename: Jacob
authors.initials: J
authors.lastname: Bar-Tana
authors.forename: Bella
authors.initials: B
authors.lastname: Kalderon
authors.forename: Marianne
authors.initials: M
authors.lastname: Suter
authors.forename: Etedal
authors.initials: E
authors.lastname: Morad
authors.forename: Dmitry
authors.initials: D
authors.lastname: Samovski
authors.forename: Dietbert
authors.initials: D
authors.lastname: Neumann
authors.forename: Rachel
authors.initials: R
authors.lastname: Hertz
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005227:Fatty Acids / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005227:Fatty Acids; D009097:Multienzyme Complexes; C526224:Prkag1 protein, mouse; C526182:PRKAB1 protein, human; C526222:PRKAG1 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human