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.