Grandmaternal exercise improves the metabolic health of second-generation offspring generated from F1 females

Maternal obesity during pregnancy can lead to increased risk for metabolic disease in offspring during adulthood, helping fuel the worldwide increase in obesity. Fortunately, studies in rodent models have established that female dams (F0) that perform voluntary wheel running exercise during pregnancy have first-generation (F1) offspring with improved glucose tolerance, suggesting a potential means to reduce the burden of generational metabolic disease transmission. We have shown that maternal exercise also affects F1 male offspring as sires, as their progeny (F2) have similarly improved metabolic health. Whether maternal exercise can affect F1 females in a manner that improves F2 offspring metabolism is not known. Here, we determined whether voluntary exercise by F0 grandmothers, via their F1 female progeny, produced F2 male and female offspring with an improved metabolic phenotype.

Six-week-old C57BL/6 N female mice (F0) were fed a chow diet and either kept sedentary or exercise trained by voluntary wheel running for 2 weeks preconception and during pregnancy. Chow-fed sedentary F1 female offspring at 8 weeks of age were bred with age-matched untreated virgin males to generate F2 offspring. F2 were kept sedentary and chow fed and studied up to 52 weeks of age. Metabolic parameters were assessed, including food intake, body weight, body composition, glucose tolerance, systemic glucose and insulin levels, and liver metabolism.

Grandmaternal exercise did not significantly alter male and female F2 offspring body weights measured throughout the first year of life, nor was there an effect of grandmaternal exercise on F2 offspring fat mass or lean mass. Remarkably, despite the lack of effect on body weight parameters, grandmaternal exercise resulted in improved glucose tolerance and homeostatic model assessment for insulin resistance (HOMA-IR) in F2 offspring at 52 weeks of age, effects that were more pronounced in male F2 offspring.

Voluntary wheel running exercise in female mice during pregnancy leads to metabolic improvements in her grand offspring, despite no direct intervention of the intermediate maternal generation. Maternal physical activity during pregnancy may reduce metabolic diseases in later generations.