Zinc-α2-Glycoprotein Knockout Influenced Genes Expression Profile in Adipose Tissue and Decreased the Lipid Mobilizing After Dexamethasone Treatment in Mice.

Zinc-α2-glycoprotein (ZAG), as an adipokine, plays an important role in lipid metabolism. However, its influence on whole gene expression profile in adipose tissue is not known. Under stress condition, how ZAG affects the lipid metabolism is also unclear. Therefore, in this study ZAG systemic knockout (KO) mice were used as a model to reveal the genes expression profile in visceral fat tissues of ZAG KO mice and wild-type mice by genome-wide microarray screening. Then dexamethasone (DEX) was used to explore the effect of ZAG deletion on body fat metabolism under stress. Our results showed that 179 genes were differentially expressed more than 1.5 times between ZAG KO mice and wild type mice, of which 26 genes were upregulated dramatically and 153 genes were significantly downregulated. Under DEX simulated stress, ZAG systemic knockout in vivo resulted in a markedly decrease of triglycerides (TG) and nonesterified fatty acid (NEFA) content in in plasma. Similarly, for lipid catabolism, ZAG KO led to a significant increase of phosphorylated HSL (p-HSL) protein and a rising tendency of adipose triglyceride lipase (ATGL) protein relative to those of the DEX group. For lipid anabolism, fatty acid synthase (FAS) and adiponectin protein expression in visceral fat rose notably in ZAG KO mice after DEX treatment. In conclusion, ZAG knockout can affect the gene expression profile of adipose tissue, reduce elevated TG and NEFA levels in plasma, and alter lipid metabolism under DEX treatment. These findings provide new insights into the mechanism of lipid metabolic disorders in response to stress.

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.

DNA Hypomethylation of GR Promoters is Associated with GR Activation and BDNF/AKT/ERK1/2-Induced Hippocampal Neurogenesis in Mice Derived From Folic-Acid-Supplemented Dams.

SCOPE: Glucocorticoid receptor (GR) mediates the nutritional programing of offspring performance. Maternal folic acid has been shown to regulate hippocampal neurogenesis and affect cognitive function in offspring, yet it remains unclear whether and how GR is involved in such effects. METHODS AND RESULTS: Adult male mice derived from dams fed basal or folic-acid-supplemented diet (5 mg folic acid/kg) throughout gestation and lactation are used in this study. Maternal folic acid significantly enhances offspring learning and memory with less fear-related behavior. Concurrently, hippocampal neurogenesis is improved with upregulation of brain-derived neurotrophic factor and its downstream AKT/ERK1/2 signaling pathway. More GR immune-positive cells are observed in hippocampus of folic acid group, which are in line with higher GR protein and mRNA abundances. Differential expression of GR exon 1 transcript variants is detected, which is inversely associated with modified DNA methylation on their alternate promoters. CONCLUSION: The results indicate that maternal folic acid supplementation promotes hippocampal neurogenesis and improves learning and memory behavior in mouse offspring. The mechanisms involve modification of DNA methylation on GR alternate promoters and GR upregulation in the hippocampus, which is associated with activation of BDNF/AKT/ERK1/2 signaling.