Laboratory of Functional Chemistry and Nutrition of Food, College of Food Science and Engineering, Northwest A&F University, Yangling, China.
Department of Food Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York, USA.
J Nutr Biochem. 2020 Sep;83:108403. doi: 10.1016/j.jnutbio.2020.108403. Epub 2020 Apr 30.
Glycolipid metabolism disorder is one of the causes of type 2 diabetes (T2D). Alternate-day fasting (ADF) is an effective dietary intervention to counteract T2D. The present study is aimed to determine the underlying mechanisms of the benefits of ADF metabolic on diabetes-induced glycolipid metabolism disorders in db/db mice. Here, leptin receptor knock-out diabetic mice were subjected to 28 days of isocaloric ADF. We found that ADF prevented insulin resistance and bodyweight gain in diabetic mice. ADF promoted glycogen synthesis in both liver and muscle. ADF also activated recombinant insulin receptor substrate-1 (IRS-1)/protein kinase B (AKT/PKB) signaling，inactivated inflammation related AMP-activated protein kinase (AMPK) and the inflammation-regulating nuclear factor kappa-B (NF-κB) signaling in the liver. ADF also suppressed lipid accumulation by inactivating the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and sterol regulatory element-binding protein-1c (SREBP-1c). Furthermore, ADF elevated the expression of fibroblast growth factor 21 (FGF21) and down-stream signaling AMPK/silent mating type information regulation 2 homolog 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in the liver of diabetic mice. The mitochondrial biogenesis and autophagy were also stimulated by ADF. Interestingly, ADF also enhanced the bile acids (BAs) metabolism by generating more cholic acid (CA), deoxycholic acid (DCA) and tauroursodeoxycholic acid (TUDCA) in db/db mice. In conclusion, ADF could significantly inhibit T2D induced insulin resistance and obesity, promote insulin signaling，reduce inflammation, as well as promote glycogen synthesis and lipid metabolism. It possibly depends on FGF21 and BA metabolism to enhance mitochondrial biosynthesis and energy metabolism.
糖脂代谢紊乱是 2 型糖尿病（T2D）的原因之一。隔日禁食（ADF）是一种有效的饮食干预措施，可对抗 T2D。本研究旨在确定 ADF 代谢对糖尿病诱导的 db/db 小鼠糖脂代谢紊乱的益处的潜在机制。在这里，瘦素受体敲除糖尿病小鼠接受了 28 天的等热量 ADF。我们发现 ADF 可预防糖尿病小鼠的胰岛素抵抗和体重增加。ADF 促进了肝脏和肌肉中的糖原合成。ADF 还激活了重组胰岛素受体底物-1（IRS-1）/蛋白激酶 B（AKT/PKB）信号，使肝脏中与炎症相关的 AMP 激活蛋白激酶（AMPK）和炎症调节核因子 kappa-B（NF-κB）信号失活。ADF 还通过抑制过氧化物酶体增殖物激活受体γ（PPAR-γ）和固醇调节元件结合蛋白-1c（SREBP-1c）的表达来抑制脂质积累。此外，ADF 通过激活成纤维细胞生长因子 21（FGF21）和下游信号 AMPK/沉默交配型信息调节 2 同源物 1（SIRT1）/过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）来提高糖尿病小鼠肝脏中的表达。ADF 还刺激线粒体生物发生和自噬。有趣的是，ADF 还通过在 db/db 小鼠中产生更多的胆酸（CA）、脱氧胆酸（DCA）和牛磺熊去氧胆酸（TUDCA）来增强胆汁酸（BA）代谢。总之，ADF 可显著抑制 T2D 诱导的胰岛素抵抗和肥胖，促进胰岛素信号，减轻炎症，以及促进糖原合成和脂质代谢。它可能依赖于 FGF21 和 BA 代谢来增强线粒体生物合成和能量代谢。
