Editors' ChoiceMetabolism

Stressed-out dads can (metabolically) stress their kids

See allHide authors and affiliations

Science Translational Medicine  02 Mar 2016:
Vol. 8, Issue 328, pp. 328ec37
DOI: 10.1126/scitranslmed.aaf3857

Stressed-out dads are clearly a torment to their children, but new research suggests that even unborn offspring aren’t protected from frazzled fathers. Genetic and environmental risk factors have historically taken center stage in the understanding of metabolic diseases such as type II diabetes. However, recent studies of nongenetic inheritance mechanisms suggest that parents’ behavioral patterns—even prior to conception—can have far reaching effects on the metabolic programming of their offspring. Stress is a common affliction of modern society and increases the risk of type II diabetes, but whether paternal stress could increase this risk in offspring was unknown. Now, Wu et al. show that in mice, paternal stress leads to hyperglycemia in offspring through up-regulation of the enzyme phosphoenolpyruvate carboxykinase (PEPCK).

Mice (the F0 generation) subjected to a daily restraint stress model for 14 days exhibited hyperglycemia, as did their offspring (F1). Abnormal pyruvate tolerance in the F1 mice, in the presence of normal insulin sensitivity, implicated hyperactive hepatic gluconeogenesis, an effect that was most prominent in F1 males. Examination of the key enzymes that regulate gluconeogenesis revealed control amounts of PEPCK mRNA but significantly increased protein levels. To investigate posttranslational regulation of gene expression, the authors conducted a hepatic microRNA (miR) microarray analysis; it revealed down-regulation of miR-466b-3p in F1 mice, which targets the PEPCK 3ʹ untranslated region. Using multiple approaches, the authors showed that miR-466b-3p represses the translation of PEPCK, preventing excess gluconeogenesis. miR-466b-3p is encoded within the Sfmbt2, a polycomb gene, and the transcription of miR-466b-3p was shown to be negatively regulated by methylation of the Sfmbt2 promoter. Indeed, increased methylation of this promoter was demonstrated in both the sperm of stressed mice and specifically in the livers of their male offspring. This pattern of methylation was replicated by injecting exogenous glucocorticoids into nonstressed male F0 mice and blocked by injecting a glucocorticoid inhibitor into stressed F0 male mice. These observations implicate stress-induced glucocorticoid release as the mechanism of inducing posttranslational regulation of PEPCK.

Although genetic and environmental risk factors are clearly important to the pathogenesis of type II diabetes, behavior patterns—including paternal stress—appear to have a deleterious effect on male offspring’s health, through nongenetic inheritance. If these findings prove true in humans, avoiding stress might be prudent not only for an individual’s health, but also for that of their children.

L. Wu et al., Paternal psychological stress reprograms hepatic gluconeogenesis in offspring. Cell Metab. 10.1016/j.cmet.2016.01.014 (2016). [Full Text]

Stay Connected to Science Translational Medicine

Navigate This Article