Mice with low levels of Shc proteins display reduced glycolytic and increased gluconeogenic activities in liver

Abstract

Shc proteins play a role in energy metabolism through interaction with the insulin receptor. The aim of this study was to determine whether Shc proteins influence liver glycolysis and gluconeogenesis under both fed and fasted states. Decreased glycolytic and increased gluconeogenic and transamination enzyme activities were observed in ShcKO versus WT mice. Levels of key regulatory metabolites, such as fructose-2,6-bisphosphate, matched the activity of metabolic pathways. Protein levels of glycolytic and gluconeogenic enzymes were not different. pAMPK protein levels increased with fasting and were higher in ShcKO versus WT mice. Therefore, Shc proteins play a role in shifting the metabolism from glucose oxidation to gluconeogenesis and lipid catabolism and should be considered as regulators of fuel selection. Fuel selection and utilization could play a critical role in healthy aging. Characterization of metabolic events in ShcKO mice would help to elucidate how metabolism is influenced by these proteins.

The influence of Shc proteins and high‐fat diet on energy metabolism of mice

“…Decreased levels of Shc proteins have been shown to produce concerted shifts in the activities of enzymes of intermediary metabolism towards an increase in capacity for fatty acid oxidation and a decrease in capacity for glycolysis , . These changes are most pronounced with fasting.…”

“…[8][9][10] The activities of regulatory enzymes of glycolysis (gluckinase/hexokinase, phosphofructokinase-1, and pyruvate kinase) were significantly decreased in liver and skeletal muscle of ShcKO compared to WT mice with fasting and 3 hours following feeding. 9,10 ShcKO mice also showed a significant increase in the activities of mitochondrial β-oxidation enzymes, although this change in enzyme activities only occurred under fasting conditions. 8 The results of these studies suggest that Shc proteins may play a role in fuel selection.…”

The biochemistry of feed efficiency, energy metabolism, and mitochondrial function, an animal and molecular approach

“…However, results indicate that there are substantial changes in energy metabolism in ShcKO mice in the fasted state . In particular, enzyme activity measurements in skeletal muscle and liver indicate a shift in metabolism towards increased capacity for fatty acid oxidation, ketogenesis, ketone body catabolism, gluconeogenesis, and amino acid catabolism, while capacity for glycolysis is decreased in ShcKO compared to WT mice under fasting conditions (Hagopian et al, 2016). These changes in enzyme activities mirror those observed in animals under caloric restriction (CR) conditions Stern et al, 2012a).…”

“…In general, the approaches associate decreased Shc levels with changes in the mitochondrial generation of ATP, regulation of mtDNA replication, energy expenditure and protection against oxidative stress in main body tissues following consumption of a HFD. It is important to note that the p66Shc knockout mice used by investigators have recently been shown to have low levels of all Shc isoforms in many tissues (Hagopian et al, 2016;. Thus, it is difficult to determine if observed changes are truly due to p66Shc or due to one of the other Shc isoforms.…”

“…In particular, Shc proteins have an important influence on energy metabolism, and studies have shown that mouse with low levels of Shc proteins (ShcKO) have lower body weight than wild-type (WT) at the same level of energy intake . In addition, Shc proteins appear to influence the fuels used for energy but they do not produce a net change in overall capacity for energy metabolism in the mitochondria (Hagopian et al, 2016). Thus, a decrease in Shc levels may help animals adapt to periods of caloric restriction or consumption of a high fat diet (HFD).…”