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  • In the past numerous studies have


    In the past, numerous studies have highlighted mother-infant interactions, whereas the fathers' legacy in shaping the metabolic landscape of offspring has drawn less attention. Notably, paternal nutritional status, exposure to drugs and toxins and even unpleasant social experiences could mediate transgenerational effects through epigenetic reprogramming [14,15]. Mechanistically, several types of epigenetic inheritance systems may play a role, including cytosine methylation, hydroxymethylation, and modifications of histone proteins such as lysine acetylation [16,17]. Small RNAs such as microRNAs (miRNAs) have also been shown to drive epigenetic inheritance. The methylation of DNA cytosine residues has been most widely studied, and many studies have shown that life-stage-specific changes in DNA methylation occur in certain metabolic genes during the fetal period and after birth. However, it remains poorly understood whether epigenetic remodeling induced by paternal exposure to hyperglycemia can be inherited and defined offspring metabolic status. Nuclear receptors are ligand-activated transcription factors (TFs) that translate information about the lipid environment into specific genetic programs, facilitating adaption to fluctuations in nutrient availability. Dysregulation of these processes can have an impact on metabolic balance, leading to obesity [18,19] and related pathologies, such as type 2 diabetes [20,21], hypertriglyceridemia [22], and nonalcoholic fatty liver disease (NAFLD) [23]. New findings increasingly support the concept that nuclear receptors are involved in transgenerational adaptive changes through epigenetic mechanisms, which reflect the impact of adverse environments in early life [24]. Peroxisome proliferator-activated receptor α (Ppara) is a key member of the PPAR family of nuclear receptors, and is highly expressed in tissues with active fatty Vorinostat (SAHA, MK0683) catabolism [25,26], especially in the liver. Its activation modulates the activities of fatty acid oxidation systems. It was reported that Ppara protects the liver from NAFLD, and its deficiency enhances hepatic steatosis and inflammation in Ppara-null mice when fed a high-fat diet (HFD) [27,28]. Several studies have demonstrated the consequences of epigenetic regulation on Ppara, specifically methylation of clusters of CpG dinucleotides in the promoter region; such methylation is induced by alterations in parental nutritional status, and perpetually reprograms metabolic hemostasis in the offspring [29,30]. As Ppara serves as a master transcriptional regulator of hepatic fatty acid metabolism, it is conceivable that its epigenetic landscape would be closely related to the transgenerational inheritance of metabolic dysfunction through the paternal lineage. In previous studies, to address the transgenerational inheritance of metabolic disorders from fathers with hyperglycemia, we produced a hyperglycemic male rat model by a single injection of low-dose streptozotocin (STZ). Then, the male rats were bred with healthy female rats to generate offspring from STZ fathers (STZ-O), for comparison with offspring from citrate buffer (CB)-treated euglycemic fathers (CB-O) [31]. Metabolic derangement has been observed in STZ-O along with increased body weight and, impaired regulation of hypothalamus mediated food intake and energy expenditure. However, the detailed molecular mechanism and physiological implications of the gene- and life stage-specific changes in DNA methylation in the fathers' lineage have not been fully addressed. In the present study, using the previous animal model, we address how paternal hyperglycemia exerts an intergenerational effect, and we further explore the underlying mechanisms. We show that the offspring of the hyperglycemic fathers develop an accumulation of fatty acid in the liver with inhibited protein expression related to fatty acid β-oxidation. Moreover, paternal hyperglycemia modifies the epigenetic signature and affects SP1-regulated transcription of Ppara by elevated DNA methylation of CpG sites in its promoter region.