Calorie restriction enhanced glycogen metabolism to compensate for lipid insufficiency

SCOPE: This study aimed to investigate the metabolic phenotype and mechanism of 40% calorie restriction (CR) in mice. METHODS AND RESULTS: CR mice exhibited super-stable blood glucose, as evidenced by increased fasting blood glucose (FBG), decreased postprandial blood glucose, and reduced glucose fluctuations. Additionally, both fasting plasma insulin and the homeostasis model assessment of insulin resistance increased significantly in CR mice. Compared with control, the phosphorylation of insulin receptor substrates-1 and serine/threonine kinase decreased in liver and fat but increased in muscle of CR mice after insulin administration, indicating hepatic and adipose insulin resistance, and muscle insulin sensitization. CR reduced visceral fat much more than subcutaneous fat. The elevated FBG was negatively correlated with low-level fasting β-hydroxybutyrate, which may result from insufficient free fatty acids and diminished ketogenic ability in CR mice. Furthermore, liver glycogen increased dramatically in CR mice. Analysis of glycogen metabolism related proteins indicated active glycogen synthesis and decomposition. Additionally, CR elevated plasma corticosterone and hypothalamic orexigenic gene expression. CONCLUSION: CR induced lipid insufficiency and stress, resulting in global physiological insulin resistance except muscle and enhanced glycogen metabolism, culminating in the stability of blood glucose manifested in increased FBG, which compensated for insufficient blood ketones.