Tissue-specific responses of IGF-1/insulin and mTOR signaling in calorie restricted rats.
Moderate calorie restriction (CR) (∼60% of ad libitum, AL, intake) has been associated with numerous favorable physiological outcomes in many species, and the insulin/IGF-1 and mTOR signaling pathways have each been proposed as potential mediators for many of CR's bioeffects. However, few studies have assessed the widely held idea that CR induces the down-regulation of the insulin/IGF-1 and/or mTOR pathways in multiple tissues. Accordingly, we analyzed the phosphorylation status of 11 key signaling proteins from the insulin/IGF-1 (IR(Tyr1162/1163), IGF-1R(Tyr1135/1136), IRS-1(Ser312), PTEN(Ser380), Akt(Ser473), GSK3α(Ser21), GSK3β(Ser9)) and mTOR (TSC2(Ser939), mTOR(Ser2448), P70S6K(Thr412), RPS6(Ser235/236)) pathways in 11 diverse tissues [liver, kidney, lung, aorta, two brain regions (cortex and cerebellum), and two slow-twitch and three fast-twitch skeletal muscles] from 9-month-old male AL and CR Fischer 344 x Brown Norway rats. The rats were studied under two conditions: with endogenous insulin levels (i.e., AL>CR) and with insulin infused during a hyperinsulinemic-euglycemic clamp so that plasma insulin concentrations were matched between the two diet groups. The most striking and consistent effect of CR was greater pAkt in 3 of the 5 skeletal muscles of CR vs. AL rats. There were no significant CR effects on the mTOR signaling pathway and no evidence that CR caused a general attenuation of mTOR signaling across the tissues studied. Rather than supporting the premise of a global downregulation of insulin/IGF-1 and/or mTOR signaling in many tissues, the current results revealed clear tissue-specific CR effects for the insulin signaling pathway without CR effects on the mTOR signaling pathway.
Muscle Biology Laboratory, School of Kinesiology, University of Michigan, Ann Arbor, Michigan, United States of America.
Naveen
N
Sharma
Carlos M
CM
Castorena
Gregory D
GD
Cartee
D000704:Analysis of Variance; D000818:Animals; D031204:Caloric Restriction; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D015309:Glucose Clamp Technique; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D007328:Insulin; D007334:Insulin-Like Growth Factor I; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases