title: Preventing the calorie restriction-induced increase in insulin-stimulated Akt2 phosphorylation eliminates calorie restriction's effect on glucose uptake in skeletal muscle.
abstract: Calorie restriction (CR; ~60% of ad libitum, AL, consumption) improves insulin-stimulated glucose uptake in skeletal muscle. The precise cellular mechanism for this healthful outcome is unknown, but it is accompanied by enhanced insulin-stimulated activation of Akt. Previous research using Akt2-null mice demonstrated that Akt2 is essential for the full CR-effect on insulin-stimulated glucose uptake by muscle. However, because Akt2-null mice were completely deficient in Akt2 in every cell throughout life, it would be valuable to assess the efficacy of transient, muscle-specific Akt inhibition for attenuation of CR-effects on glucose uptake. Accordingly, we used a selective Akt inhibitor (MK-2206) to eliminate the CR-induced elevation in insulin-stimulated Akt2 phosphorylation and determined the effects on Akt substrates and glucose uptake. We incubated isolated epitrochlearis muscles from 9-month-old AL and CR (~60-65% of AL intake for 6months) rats with or without MK-2206 and measured insulin-stimulated (1.2nM) glucose uptake and phosphorylation of the insulin receptor (Tyr1162/1163), pan-Akt (Thr308 and Ser473), Akt2 (Thr308 and Ser473), AS160/TBC1D4 (Thr642), and Filamin C (Ser2213). Incubation of isolated skeletal muscles with a dose of a selective Akt inhibitor that eliminated the CR-induced increases in Akt2 phosphorylation prevented CR's effects on insulin-stimulated glucose uptake, pAS160(Thr642) and pFilamin C(Ser2213) without altering pIR(Tyr1162/1163). These data provide compelling new evidence linking the CR-induced increase in insulin-stimulated Akt2 phosphorylation to CR's effects on insulin-mediated phosphorylation of Akt substrates and glucose uptake in skeletal muscle.
authors: Muscle Biology Laboratory, School of Kinesiology, University of Michigan, Ann Arbor, MI 48109-2214, USA. naveens@umich.edu
authors: Naveen
authors: N
authors: Sharma
authors: Edward B
authors: EB
authors: Arias
authors: Donel A
authors: DA
authors: Sequea
authors: Gregory D
authors: GD
authors: Cartee
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D003285:Contractile Proteins / Q000378:metabolism; D064448:Filamins; D005947:Glucose / Q000378:metabolism*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D006575:Heterocyclic Compounds, 3-Ring; D007328:Insulin; C548887:MK 2206; D008840:Microfilament Proteins; D011972:Receptor, Insulin; C494923:Akt2 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose