Diabetes is abruptly increased in the past decades in China. Both genetic and environmental risk factors play major roles in the development of diabetes. People's Lifestyle has dramatically changed in China. The mean body mass index in population has been increase by 1.8 kg/m2 and obesity prevalence increased by 8 folds in the past 30 years. In general, the environmental risk factors, including overnutrition and less physical exercise contributes to the rapid increase of diabetes in China.
Epigenetic modifications, including DNA methylation, histone modification and non-coding RNA can respond to environmental change and further regulate gene expression and function. Thus, epigenetic modifications sense and respond to the change of nutrition, stress, and further regulate those critical gene expression and function in metabolism.
Psychological stress is prevalent in modern society. Both epidemiologic and experimental animal studies demonstrate that chronic psychological stress exerts adverse effects on the initiation and/or progression of diabetes. However, transgenerational effects of this environmental information remains poorly understood. Here, using a mouse model of restraint stress, we show that paternal stress exposure reprograms hepatic gluconeogenesis in the resulting offspring. Relative to controls, adult offspring fathered by stressed males exhibit hyperglycemia as a result of enhanced hepatic gluconeogenesis. At the molecular level, we identify an epigenetic alteration in the Sfmbt2 gene promoter from sperm of stressed fathers and liver of their offspring, which results in a reduced expression of microRNA-466b-3p. Gain- and loss-of-function studies demonstrate that down-regulation of microRNA-466b-3p leads to an elevated PEPCK protein level, a key enzyme necessary for gluconeogenesis. Therefore, we provide evidence showing the transgenerational effects of paternal psychological stress on the regulation of glucose metabolism in the offspring.