Abstract
We previously reported that molecular hydrogen (H2) acts as a novel antioxidant to exhibit multiple functions. Moreover, long-term drinking of H2-water (water infused with H2) enhanced energy expenditure to improve obesity and diabetes in db/db mice accompanied by the increased expression of fibroblast growth factor 21 (FGF21) by an unknown mechanism. H2 was ingested by drinking of H2-water or by oral administration of an H2-producing material, MgH2. The comprehensive gene expression profile in the liver of db/db mice was analyzed by DNA microarray. The molecular mechanisms underlying the gene expression profile was investigated using cultured HepG2 cells. Moreover, the effects on lifespan of drinking H2-water were examined using wild-type mice that were fed a fatty diet. Pathway analyses based on comprehensive gene expression revealed the increased expression of various genes involved in fatty acid and steroid metabolism. As a transcription pathway, the PPARα signaling pathway was identified to upregulate their genes by ingesting H2. As an early event, the gene expression of PGC-1α was transiently increased, followed by increased expression of FGF21. The expression of PGC-1α might be regulated indirectly through sequential regulation by H2, 4-hydroxy-2-nonenal, and Akt/FoxO1 signaling, as suggested in cultured cell experiments. In wild-type mice fed the fatty diet, H2-water improved the level of plasma triglycerides and extended their average of lifespan. H2 induces expression of the PGC-1α gene, followed by stimulation of the PPARα pathway that regulates FGF21, and the fatty acid and steroid metabolism.
Highlights
We previously reported that molecular hydrogen (H2) acts as a novel antioxidant and effectively protects cells against oxidative stress.[1]
Our previous study indicated that 3 months of consumption of H2-water improved obesity and diabetes in db/db mice accompanied by increased expression of the fibroblast growth factor 21 (FGF21) gene; the causal association among their improved phenotypes, stimulated energy metabolism, and gene expression was unclear because of their long-term mutual interactions
FGF21 is PGC-1α dependently transcribed by peroxisome proliferator-activated receptor α (PPARα), while FGF21
Summary
We previously reported that molecular hydrogen (H2) acts as a novel antioxidant and effectively protects cells against oxidative stress.[1]. In addition to anti-oxidative roles, we reported the benefit of ad libitum drinking of H2-water (water infused with H2) for type 2 diabetes using db/db obesity model mice that lack the functional leptin receptor.[6] Long-term drinking of H2-water significantly decreased body and fat weights, and the levels of plasma glucose, insulin, and triglyceride. (FGF21), which is known to function to enhance fatty acid and glucose expenditure.[6] On the other hand, the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, catalytic subunit (G6PC) genes involved in gluconeogenesis were not affected.[6] These results suggest the potential benefit of H2 in improving obesity, diabetes, and metabolic syndrome. We show that drinking H2-water improved plasma triglycerides and extended the average of lifespan of the wild-type mice that were fed a fatty diet
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