Intermittent Fasting–Improved Glucose Homeostasis Is Not Entirely Dependent on Caloric Restriction in db/db Male Mice

Intermittent fasting (IF), which involves prolonged fasting intervals accompanied by caloric restriction (CR), is an effective dietary treatment for obesity and diabetes. Although IF offers many benefits, it is difficult to determine whether these benefits are the consequences of CR. Every-other-day feeding (EODF) is a commonly used IF research model. This study was designed to identify factors, in addition to CR, responsible for the effects of EODF and the possible underlying mechanisms. Diabetic db/db mice were divided into three groups: ad libitum (AL), meal feeding (MF), and EODF. The MF model was used to attain a level of CR comparable to that of EODF, with food distribution evenly divided between 10:00 a.m. and 6:00 p.m., thereby minimizing the fasting interval. EODF yielded greater improvements in glucose homeostasis than MF in db/db mice by reducing fasting glucose levels and enhancing glucose tolerance. However, these effects on glucose metabolism were less pronounced in lean mice. Furthermore, ubiquitination of the liver-specific glucocorticoid (GC) receptor (GR) facilitated its degradation and downregulation of Kruppel-like factor 9 (KLF9), which ultimately suppressed liver gluconeogenesis in diabetic EODF mice. Although GR and KLF9 might mediate the metabolic benefits of EODF, the potential benefits of EODF might be limited by elevated serum GC levels in diabetic EODF mice. Overall, this study suggests that the metabolic benefits of EODF in improving glucose homeostasis are independent of CR, possibly because of the downstream effects of liver-specific GR degradation.