Alternate-day fasting alleviates diabetes-induced glycolipid metabolism disorders: roles of FGF21 and bile acids

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.