Caloric restriction in C57BL/6J mice mimics therapeutic fasting in humans

Background: Caloric restriction (CR) has long been recognized as a dietary therapy that improves health and increases longevity. Little is known about the persistent effects of CR on plasma biomarkers (glucose, ketone bodies, and lipids) following re-feeding in mice. It is also unclear how these biomarker changes in calorically restricted mice relate to those observed previously in calorically restricted humans. Results: Three groups of individually housed adult female C57BL/6J (B6) mice (n = 4/group) were fed a standard rodent chow diet either: (1) unrestricted (UR); (2) restricted for three weeks to reduce body weight by approximately 15-20% (R); or (3) restricted for three weeks and then re-fed unrestricted (ad libitum) for an additional three weeks (R-RF). Body weight and food intake were measured throughout the study, while plasma lipids and levels of glucose and ketone bodies (beta hydroxybutyrate) were measured at the termination of the study. Plasma glucose, phosphatidylcholine, cholesterol, and triglycerides were significantly lower in the R mice than in the UR mice. In contrast, plasma fatty acids and beta-hydroxybutyrate were significantly higher in the R mice than in the UR mice. CR had no effect on plasma phosphatidylinositol levels. While body weight and plasma lipids of the R-RF mice returned to unrestricted levels upon re-feeding, food intake and glucose levels remained significantly lower than those prior to the initiation of CR. Conclusion: CR establishes a new homeostatic state in B6 mice that persists for at least three weeks following ad libitum re-feeding. Moreover, the plasma biomarker changes observed in B6 mice during CR mimic those reported in humans on very low calorie diets or during therapeutic fasting.