Paternal long‐term exercise programs offspring for low energy expenditure and increased risk for obesity in mice

Abstract

Obesity has more than doubled in children and tripled in adolescents in the past 30 yr. The association between metabolic disorders in offspring of obese mothers with diabetes has long been known; however, a growing body of research indicates that fathers play a significant role through presently unknown mechanisms. Recent observations have shown that changes in paternal diet may result in transgenerational inheritance of the insulin-resistant phenotype. Although diet-induced epigenetic reprogramming via paternal lineage has recently received much attention in the literature, the effect of paternal physical activity on offspring metabolism has not been adequately addressed. In the current study, we investigated the effects of long-term voluntary wheel-running in C57BL/6J male mice on their offspring's predisposition to insulin resistance. Our observations revealed that fathers subjected to wheel-running for 12 wk produced offspring that were more susceptible to the adverse effects of a high-fat diet, manifested in increased body weight and adiposity, impaired glucose tolerance, and elevated insulin levels. Long-term paternal exercise also altered expression of several metabolic genes, including Ogt, Oga, Pdk4, H19, Glut4, and Ptpn1, in offspring skeletal muscle. Finally, prolonged exercise affected gene methylation patterns and micro-RNA content in the sperm of fathers, providing a potential mechanism for the transgenerational inheritance. These findings suggest that paternal exercise produces offspring with a thrifty phenotype, potentially via miRNA-induced modification of sperm.

Homage to the ‘H’ in developmental origins of health and disease

“…In the case of paternal exercise, the two current studies yield conflicting data with one reporting positive effects on cognitive function 61 but another suggesting this paternal activity results in offspring metabolic disruptions. 62 Clearly, additional studies are needed to sort out the potential offspring DOHaD outcomes due to paternal exercise and whether there can be transgenerational transmission due to epigenetic changes in the spermatozoa. 62 While fathers cannot provide direct nourishment to the young after birth, additional attention should be paid to whether a healthy diet of the father, and the mother, before conception can lead to long-term beneficial offspring consequences.…”

“…62 Clearly, additional studies are needed to sort out the potential offspring DOHaD outcomes due to paternal exercise and whether there can be transgenerational transmission due to epigenetic changes in the spermatozoa. 62 While fathers cannot provide direct nourishment to the young after birth, additional attention should be paid to whether a healthy diet of the father, and the mother, before conception can lead to long-term beneficial offspring consequences. It is increasingly becoming apparent that sub-optimal paternal diets, those high in fat or protein restricted, can result in negative offspring sequelae, [14][15][16][17][18][19][20][21][146][147][148][149] but the impacts of a healthy diet have been largely ignored.…”

“…61 In contrast, another mouse study found that males who exercised 12 weeks before mating gave rise to offspring more vulnerable to deleterious effects induced by a HFD, as exemplified by increased in body weight, adiposity, impaired glucose tolerance and elevated insulin levels. 62 Further, several metabolic genes (Ogt, Oga, Pdk4, H19, Glut4 and Ptpn1) are up-regulated in the skeletal muscle of offspring whose fathers underwent long-term exercise. The sperm of exercised fathers harbors DNA methylation and micro-RNA changes, which may lead to transgenerational propagation of the above metabolic changes.…”

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…Paternally-induced transgenerational inheritance for obesity and metabolic disorders has also been confirmed in mammals. Changes in paternal diet and fitness have been shown to initiate environmental reprogramming and promote obesity susceptibility and phenotype variation in mice and humans (Carone et al, 2010;Murashov et al, 2015;Soubry, 2015), providing more insights into the mechanisms behind intergenerational reprogramming and phenotypic variations for obesity and metabolic disorders.…”

The role of diet and exercise in the transgenerational epigenetic landscape of T2DM

“…Evidence from numerous animal studies suggests that regular exercise training by either the mother or the father confers a health benefit on the first generation [56][57][58][59] . Nevertheless, little is known about the mechanism by which exercise effects various metabolic phenotypes over several generations.…”