The Influence of Shc Proteins on the Whole Body Energetic Response to Calorie Restriction Initiated in 3-Month-Old Mice

There is increasing evidence that Shc proteins play a role in energy metabolism, and we have previously reported that knockdown of Shc proteins influences the energetic response to acute (3 days) calorie restriction (CR) in 18-month-old mice. Whether Shc proteins play a role in the metabolic response to CR in younger mice has yet to be elucidated. Hence, we sought to determine the impact of 3 days and longer term (2 months) CR on energy expenditure (EE) and respiratory quotient (RQ) in 3 month-old Shc knockout (ShcKO) and wild-type (WT) mice. ShcKO mice decreased (P < 0.001) EE normalized for body weight ( ) by 3 days of CR, while no such change was observed in WT animals. However, both ShcKO and WT mice decreased (P < 0.001) at 2 months of CR and there were no differences in body weight between the ShcKO and WT mice at either 3 days or 2 months of CR. Consistent with increased fatty acid oxidation, only ShcKO mice maintained decreased (P < 0.001) 24？h RQ through 2 months of CR, suggesting that they were able to maintain increased fatty acid oxidation for a longer period of time than WT mice. These results indicate that Shc proteins may contribute to some of the acute energetic responses to CR. 1. Introduction Shc proteins act as adaptor molecules which specifically bind to phosphorylated tyrosine residues on the cytoplasmic motif of growth factor receptors, thereby serving as mitogenic signaling molecules. Three splice variants (p46Shc, p52Shc, and p66Shc) are encoded by the mammalian Shc locus. The p66Shc(？/？) mouse has been a common model used to investigate the possible role p66Shc plays in energy metabolism and aging. However, it has recently been shown [1] that the levels of both the p52Shc and p46Shc isoforms are also substantially decreased in liver and skeletal muscle from these animals. Thus, these mice (we refer to as ShcKO) provide a model of overall decreases in Shc protein levels in muscle, liver, and other tissues. While it has been proposed that the p66Shc isoform may play a role in the aging process [2], it is also well established that Shc proteins play a role in insulin signaling [3, 4]. Furthermore, it has been proposed that Shc may influence aging through alterations in insulin signaling, adiposity, and energy metabolism [1, 5]. Still, the overall impact of Shc proteins on energy metabolism is not entirely clear. Previous overfeeding studies in young (2-3？months) mice demonstrated that ShcKO may mitigate weight gain in response to overnutrition. It has been reported that body weights are lower in ShcKO compared to wild-type (WT)