Caloric restriction alters the feeding response of key metabolic enzyme genes

Differential 'fuel usage' has been proposed as a mechanism for life-span ex tension by caloric restriction (CR). Here, we report the effects of CR, ini tiated after weaning, on metabolic enzyme gene expression 0, 1.5, 5, and 12 h after feeding of 24-month-old mice. Plasma glucose and insulin were redu ced by similar to 20 and 80%. Therefore, apparent insulin sensitivity, as j udged by the glucose to insulin ratio, increased 3.3-fold in CR mice. Phosp hoenolpyruvate carboxykinase mRNA and activity were transiently reduced 1.5 h after feeding, but were 20-100% higher in CR mice at other times. Glucos e-6-phosphatase mRNA was induced in CR mice and repressed in control mice b efore, and for 5 h following feeding. Feeding transiently induced glucokina se mRNA fourfold in control mice, but only slightly in CR mice. Pyruvate ki nase and pyruvate dehydrogenase activities were reduced similar to 50% in C R mice at most times. Feeding induced glutaminase mRNA, and carbamyl phosph ate synthetase I and glutamine synthase activity (and mRNA). They were each similar to twofold or higher in CR mice. These results indicate that in mi ce, CR maintains higher rates of gluconeogenesis and protein catabolism, ev en in the hours after feeding. The data are consistent with the idea that C R continuously promotes the turnover and replacement of extrahepatic protei ns. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.