Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring

• Published in: Cell metabolism 2016-04, Vol.23 (4), p.735-743
• Main Authors: Wu, Ling, Lu, Yan, Jiao, Yang, Liu, Bin, Li, Shangang, Li, Yao, Xing, Fengying, Chen, Dongbao, Liu, Xing, Zhao, Jiejie, Xiong, Xuelian, Gu, Yanyun, Lu, Jieli, Chen, Xuejin, Li, Xiaoying
• Format: Article
• Language: English
• Subjects: Animals; DNA Methylation; Gene Expression Regulation; Gluconeogenesis; Hyperglycemia - etiology; Hyperglycemia - genetics; Hyperglycemia - metabolism; Hyperglycemia - physiopathology; Liver - metabolism; Liver - physiopathology; Male; Mice, Inbred C57BL; MicroRNAs - genetics; Phosphoenolpyruvate Carboxykinase (ATP) - genetics; Phosphoenolpyruvate Carboxykinase (ATP) - metabolism; Promoter Regions, Genetic; Stress, Psychological - complications; Stress, Psychological - genetics; Stress, Psychological - metabolism; Stress, Psychological - physiopathology; Transcription Factors - genetics
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.01.014

Both epidemiologic and experimental animal studies demonstrate that chronic psychological stress exerts adverse effects on the initiation and/or progression of many diseases. However, intergenerational effects of this environmental information remains poorly understood. Here, using a C57BL/6 mouse model of restraint stress, we show that offspring of stressed fathers exhibit hyperglycemia due to enhanced hepatic gluconeogenesis and elevated expression of PEPCK. Mechanistically, we identify an epigenetic alteration at the promoter region of the Sfmbt2 gene, a maternally imprinted polycomb gene, leading to a downregulation of intronic microRNA-466b-3p, which post-transcriptionally inhibits PEPCK expression. Importantly, hyperglycemia in F1 mice is reversed by RU486 treatment in fathers, and dexamethasone administration in F0 mice phenocopies the roles of restraint stress. Thus, we provide evidence showing the effects of paternal psychological stress on the regulation of glucose metabolism in offspring, which may have profound implications for our understanding of health and disease risk inherited from fathers. [Display omitted] •Paternal psychological stress promotes hepatic gluconeogenesis in offspring•Reduced expression of miR-466b-3p increases PEPCK protein contents in stress-F1 mice•Promoter hypermethylation of the Sfmbt2 gene leads to downregulation of miR-466b-3p•Paternal elevated glucocorticoids contribute to hyperglycemia in offspring Using a mouse model of restraint stress, Wu et al. uncover the intergenerational effects of paternal psychological stress on glucose metabolism in offspring. Paternal stress epigenetically downregulates miR-466b-3p expression, leading to increased PEPCK expression and hepatic gluconeogenesis in hyperglycemic F1 mice.