Altered nutrient response of mTORC1 as a result of changes in REDD1 expression: effect of obesity vs. REDD1 deficiency

Abstract

Although aberrant mTORC1 signaling has been well established in models of obesity, little is known about its repressor, REDD1. Therefore, the initial goal of this study was to determine the role of REDD1 on mTORC1 in obese skeletal muscle. REDD1 expression (protein and message) and mTORC1 signaling (S6K1, 4E-BP1, raptor-mTOR association, Rheb GTP) were examined in lean vs. ob/ob and REDD1 wild-type (WT) vs. knockout (KO) mice, under conditions of altered nutrient intake [fasted and fed or diet-induced obesity (10% vs. 60% fat diet)]. Despite higher ( P < 0.05) S6K1 and 4E-BP1 phosphorylation, two models of obesity ( ob/ob and diet-induced) displayed elevated ( P < 0.05) skeletal muscle REDD1 expression compared with lean or low-fat-fed mouse muscle under fasted conditions. The ob/ob mice displayed elevated REDD1 expression ( P < 0.05) that coincided with aberrant mTORC1 signaling (hyperactive S6K1, low raptor-mTOR binding, elevated Rheb GTP; P < 0.05) under fasted conditions, compared with the lean, which persisted in a dysregulated fashion under fed conditions. REDD1 KO mice gained limited body mass on a high-fat diet, although S6K1 and 4E-BP1 phosphorylation remained elevated ( P < 0.05) in both the low-fat and high-fat-fed KO vs. WT mice. Similarly, the REDD1 KO mouse muscle displayed blunted mTORC1 signaling responses (S6K1 and 4E-BP1, raptor-mTOR binding) and circulating insulin under fed conditions vs. the robust responses ( P < 0.05) in the WT fed mouse muscle. These studies suggest that REDD1 in skeletal muscle may serve to limit hyperactive mTORC1, which promotes aberrant mTORC1 signaling responses during altered nutrient states.