Stressed dads give offspring high blood sugar

Mouse fathers under psychological stress were more likely to have offspring with high blood sugar than unstressed dads.

In a study appearing February 18 in Cell Metabolism, researchers linked epigenetic or environmental influences, to changes in a stressed dad's sperm — changes that they could be prevented by blocking the father's stress hormones.

The study adds to growing evidence that a male's psychological stress can be passed down to his offspring through his genetic code.

"We are very interested in how behavioral change affects glucose homeostasis [stability]," says co-senior author Xiaoying Li, an endocrinologist at the Shanghai Jiao Tong University School of Medicine and Rui-Jin Hospital, China. "Epidemiological studies have demonstrated the association of psychological stress with incidental diabetes. We were curious about whether the effect can be passed down through generations."

To induce stress, Li and her colleagues confined male mice in plastic tubes for 2 hr a day, for 2 consecutive weeks. Afterwards, the animals' glucose levels increased, they gained weight and had increased levels of stress hormones called glucocorticoids in their blood. These mice were then mated with females that hadn't been stressed. The resulting offspring had higher blood glucose than normal. Adds Li: "Paternal psychological stress can result in hyperglycemia [an excess of glucose in the bloodstream, often associated with diabetes mellitus] in their offspring."

The root of the increased blood sugar was via a gene called Sfmbt2. When a male mouse is immobilized daily in a plastic tube, the spike of glucocorticoids causes extra methyl groups to attach to the Sfmbt2 gene in his sperm.

These epigenetic marks don't affect the underlying structure of DNA, but they do control how active Sfmbt2 and an associated microRNA (the intronic microRNA-466b-3p) are (a function called expression).

"The epigenetic reprogramming by stress, through glucocorticoids, was surprising," says other senior co-author Xuejin Chen, also at the Shanghai Jiao Tong University School of Medicine.

In stressed fathers epigenetic change showed up in their offspring's livers.

Intronic microRNA-466b-3p — made from the Sfmbt2 gene — helps regulate an enzyme called PEPCK to control sugar production in the liver. When mammals reproduce, Sfmbt2 is turned off in the egg — all offspring inherit their only working copy from their father's sperm.

If the only functional Sfmbt2 gene carries attached methyl groups (or epigenetic tags) induced by stress, intronic microRNA-466b-3p is silenced/turned off, and can't regulate PEPCK as it normally would. The offspring of that father then produce too much PEPCK in their livers as well, causing their blood sugar to rise.

By understanding the mechanism of this gene/protein pathway, researchers hope to one day inject male mice with a molecule to stop methyl groups from attaching to the Sfmbt2 gene. That will dampen the glucocorticoid effect.

"It is possible, in the future, our study will be translated into treatment for hyperglycemia in human beings."

Xiaoying Li PhD, Endocrinologist, Shanghai Institute of Endocrinology and Metabolism, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, China

Abstract
Type 2 diabetes has become a major public health concern worldwide. Although gene-environment interactions contribute to hyperglycemia, increasing evidence indicates that maternal and paternal inductions of intergenerational responses are also important (Somer and Thummel, 2014). Specifically, the effects of father-to-offspring transmission attract recent attention. It has been noted that changes in paternal diets, including food deprivation (Anderson et al., 2006), and the modulation of fat (Ng et al., 2010), protein (Carone et al., 2010), and sugar (st et al., 201) are implicated in the metabolic programming of the resulting offspring. Mechanistically, altered DNA methylation and histone modifications, as well as changed expression of small non-coding RNAs, have been reported to mediate this inter/transgenerational effect (Carone et al., 2010, Radford et al., 2014, Martínez et al., 2014, Gapp et al., 2014a). However, it remains poorly understood whether epigenetic remodeling induced by paternal exposure to other types of environmental information can be inherited and define offspring metabolic states.

Psychological stress is common in our modern society (Oken et al., 2015). Epidemiologic and/or experimental animal studies demonstrate that prolonged stress increases risk for many health problems, including neuropsychiatric disorders (Lupien et al., 2009), tumorigenesis (Thaker et al., 2006), and type 2 diabetes (Chandola et al., 2006). Interestingly, it has been reported that maternal stress, such as stress experienced during pregnancy (Entringer et al., 2012), could alter body weight and glucose metabolism in offspring. However, it is unclear whether paternal stress could affect glucose metabolism in their offspring.

In the present study, using a mouse model of restraint stress (Bali and Jaggi, 2015), we address how paternal stress exerts an intergenerational effect in mammals, and we further explore the underlying mechanisms. We show that the offspring of stressed fathers have elevated blood glucose concentrations and hepatic gluconeogenesis with increased protein expression of phosphoenolpyruvate carboxykinase (PEPCK). Moreover, paternal stress modifies an epigenetic signature and downregulates expression of a specific microRNA (miRNA) that targets the 3′ UTR of PEPCK.

This study was supported by grants from the National Key Basic Research Program of China and the China Natural Science Foundation.

Cell Metabolism, Wu, Lu, and Jiao et al.: "Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring" http://dx.doi.org/10.1016/j.cmet.2016.01.014

Cell Metabolism (@Cell_Metabolism), published by Cell Press, is a monthly journal that publishes reports of novel results in metabolic biology, from molecular and cellular biology to translational studies. The journal aims to highlight work addressing the molecular mechanisms underlying physiology and homeostasis in health and disease. For more information, please visit http://www.cell.com/cell-metabolism. To receive Cell Press media alerts, contact press@cell.com.

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This graph shows how methyl groups (M) when added to a DNA chain stop the production of intronic microRNA-466b-3p, leading to increased PEPCK production and hepatic blood sugar to rise in F1 mice.
Image Credit: Wu, Lu, and Jiao et al./Cell Metabolism 2016