Intermittent fasting (IF), which involves prolonged fasting intervals accompanied by caloric restriction, 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 caloric restriction. Every-other-day feeding (EODF) is a commonly used IF research model. This study was designed to identify other effectors of EODF, in addition to caloric restriction, 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 employed to attain a level of caloric restriction comparable to EODF, with food distribution evenly divided between 10 AM and 6 PM, 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 liverspecific glucocorticoid receptor (GR) facilitated its degradation, and downregulating 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 glucocorticoid (GC) levels in diabetic EODF mice. Overall, this study suggests that the metabolic benefits of EODF in improving glucose homeostasis are independent of caloric restriction, possibly due to the downstream effects of liver-specific GR degradation.

This article contains supplementary material online at https://doi.org/10.2337/figshare.25418539.

This content is only available via PDF.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license.

Article PDF first page preview

Article PDF first page preview