Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1α to enhance fatty acid metabolism

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. Oral consumption of molecular hydrogen (H2) activates genes with a critical role in fatty acid metabolism. H2 can prevent the cellular damage caused by oxidizing chemical compounds, and a previous study suggested that water infused with H2 can improve metabolic health in genetically obese rodents. In order to identify a potential mechanism of action, researchers led by Shigeo Ohta at Nippon Medical School dosed obese mice with H2-infused water for two weeks. Before the animals'' health did not notably change, the researchers observed clear changes in the expression of several genes in a pathway that regulate the metabolism of steroids and fatty acids in the liver. This treatment was also associated with lower blood triglycerides in genetically normal mice fed a high-fat diet, suggesting that such treatments could induce a clinically useful metabolic response.