Betaine Alleviates High-Fat Diet-Induced Disruptionof Hepatic Lipid and Iron Homeostasis in Mice.

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat deposition in the liver, which is often associated with disrupted iron homeostasis. Betaine has been reported to be hepatoprotective, yet whether and how betaine ameliorates high-fat diet-induced disruption of hepatic lipid and iron homeostasis remains elusive. In this study, mice were fed either standard (CON) or high-fat diet (HFD) for 9 weeks to establish a NAFLD model. Mice raised on HF diet were then assigned randomly to HF and HFB groups, HFB group being supplemented with 1% (w/v) of betaine in the drinking water for 13 weeks. Betaine supplementation significantly alleviated excessive hepatic lipid deposition and restored hepatic iron content. Betaine partly yet significantly reversed HFD-induced dysregulation of lipogenic genes such as PRARγ and CD36, as well as the iron-metabolic genes including FPN and HAMP that encodes hepcidin. Similar mitigation effects of betaine were observed for BMP2 and BMP6, the up-stream regulators of hepcidin expression. Betaine significantly rectified disrupted expression of methyl transfer gene, including BHMT, GNMT and DNMT1. Moreover, HFD-modified CpG methylation on the promoter of PRARγ and HAMP genes was significantly reversed by betaine supplementation. These results indicate that betaine alleviates HFD-induced disruption of hepatic lipid and iron metabolism, which is associated with modification of CpG methylation on promoter of lipogenic and iron-metabolic genes.

GR-mediated transcriptional regulation of m6A metabolic genes contributes to diet-induced fatty liver in hens.

BACKGROUND: Glucocorticoid receptor (GR) mediated corticosterone-induced fatty liver syndrome (FLS) in the chicken by transactivation of Fat mass and obesity associated gene (FTO), leading to demethylation of N6-methyladenosine (m6A) and post-transcriptional activation of lipogenic genes. Nutrition is considered the main cause of FLS in the modern poultry industry. Therefore, this study was aimed to investigate whether GR and m6A modification are involved in high-energy and low protein (HELP) diet-induced FLS in laying hens, and if true, what specific m6A sites of lipogenic genes are modified and how GR mediates m6A-dependent lipogenic gene activation in HELP diet-induced FLS in the chicken. RESULTS: Laying hens fed HELP diet exhibit excess (P < 0.05) lipid accumulation and lipogenic genes activation in the liver, which is associated with significantly increased (P < 0.05) GR expression that coincided with global m6A demethylation. Concurrently, the m6A demethylase FTO is upregulated (P < 0.05), whereas the m6A reader YTHDF2 is downregulated (P < 0.05) in the liver of FLS chickens. Further analysis identifies site-specific demethylation (P < 0.05) of m6A in the mRNA of lipogenic genes, including FASN, SREBP1 and SCD. Moreover, GR binding to the promoter of FTO gene is highly enriched (P < 0.05), while GR binding to the promoter of YTHDF2 gene is diminished (P < 0.05). CONCLUSIONS: These results implicate a possible role of GR-mediated transcriptional regulation of m6A metabolic genes on m6A-depenent post-transcriptional activation of lipogenic genes and shed new light in the molecular mechanism of FLS etiology in the chicken.

Melatonin alleviates hippocampal GR inhibition and depression-like behavior induced by constant light exposure in mice.

Light pollution has become a potential health risk factor worldwide. Chronic exposure to constant light (CCL) leads to depressive-like behavior, yet the mechanism remains unclear. In this study, mice exposed to CCL for 3 weeks exhibited depression-like behaviors, with decreased melatonin in plasma and increased oxidative stress in hippocampus. Meanwhile, CCL-exposed mice showed elevated plasma corticosterone (CORT) levels and diminished glucocorticoid receptor (GR) phosphorylation in hippocampus. Concurrently, glycogen synthase kinase 3 beta (GSK3ß) was inactivated with increased phosphorylation at Ser9. The interrelationship of GSK3ß and GR was clarified in mouse hippocampal neuron (HT-22) cells. GSK3ß inhibitor CHIR-99021 induced GR inhibition with diminished phosphorylation, while GR inhibitor RU486 did not affect GSK3ß expression or phosphorylation. Furthermore, GSK3ß-mediated GR inhibition was reproduced in vitro in HT-22 cells treated with melatonin receptor antagonist luzindole and H2O2 in combination. Finally, melatonin reversed GSK3ß-mediated GR inhibition in hippocampus and improved CCL-induced depression-like behavior in mice. These results indicate that CCL induces melatonin deficiency and oxidative stress in hippocampus, which in turn leads to GSK3ß-mediated GR inhibition and depression-like behavior in mice.

Transgenerational Inheritance of Betaine-Induced Epigenetic Alterations in Estrogen-Responsive IGF-2/IGFBP2 Genes in Rat Hippocampus.

SCOPE: Betaine serves as a methyl donor for DNA methylation. Here, the effects of betaine on hippocampal expression of neurogenesis genes and their DNA methylation status across three generations are investigated. METHODS AND RESULTS: Pregnant rats (F0) are fed control and betaine-supplemented diets throughout gestation and lactation. Female F1 and F2 offspring at weaning, together with the F0 dams, are used in the study. Hippocampal expression of aromatase, estrogen receptor α, and estrogen-related receptor ß is downregulated in F1, together with the estrogen-responsive insulin-like growth factor 2/insulin-like growth factor binding protein 2 (IGF-2/IGFBP2) genes. However, all these genes are upregulated in F2, which follows the same pattern of F0. In agreement with changes in mRNA expression, the imprinting control region (ICR) of IGF-2 gene is hypomethylated in F1 but hypermethylated in F2 and F0. In contrast, the promoter DNA methylation status of all the affected genes is hypermethylated in F1 but hypomethylated in F2 and F0. Methyl transfer enzymes, such as betaine homocysteine methyltransferase and DNA methyltransferase 1, follow the same pattern of transgenerational inheritance. CONCLUSION: These results indicate that betaine exerts a transgenerational effect on hippocampal expression of estrogen-responsive genes in rat offspring, which is associated with corresponding alterations in DNA methylation on ICR of IGF-2 gene and the promoter of affected genes.