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.

中文翻译：

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间歇性禁食改善 db/db 雄性小鼠的葡萄糖稳态并不完全依赖于热量限制

间歇性禁食（IF）涉及延长禁食间隔并限制热量，是治疗肥胖和糖尿病的有效饮食方法。尽管间歇性禁食有很多好处，但很难确定这些好处是否是热量限制的结果。隔日喂养（EODF）是一种常用的 IF 研究模型。本研究旨在确定除了热量限制之外的 EODF 的其他效应器以及可能的潜在机制。糖尿病db/db小鼠被分为三组：随意采食（AL）、膳食喂养（MF）和EODF。采用 MF 模型来达到与 EODF 相当的热量限制水平，食物分配均匀地分布在上午 10 点到下午 6 点之间，从而最大限度地缩短禁食间隔。在 db/db 小鼠中，EODF 通过降低空腹血糖水平和增强葡萄糖耐量，比 MF 更能改善葡萄糖稳态。然而，这些对葡萄糖代谢的影响在瘦小鼠中不太明显。此外，肝脏特异性糖皮质激素受体 (GR) 的泛素化促进了其降解，并下调了 Kruppel 样因子 9 (KLF9)，最终抑制了糖尿病 EODF 小鼠的肝脏糖异生。尽管 GR 和 KLF9 可能介导 EODF 的代谢益处，但 EODF 的潜在益处可能会受到糖尿病 EODF 小鼠血清糖皮质激素 (GC) 水平升高的限制。总体而言，这项研究表明，EODF 在改善葡萄糖稳态方面的代谢益处与热量限制无关，这可能是由于肝脏特异性 GR 降解的下游影响。