Exercise-induced 3'-sialyllactose in breast milk is a critical mediator to improve metabolic health and cardiac function in mice offspring

Authors: HARRIS, JOHAN - The Ohio State University; PINCKARD, KELSEY - The Ohio State University; WRIGHT, KATHERINE - The Ohio State University; BAER, LISA - The Ohio State University; ARTS, PETER - The Ohio State University; ABAY, EAMAN - The Ohio State University; SHETTIGAR, VIKRAM - The Ohio State University; LEHNIG, ADAM - The Ohio State University; ROBERSTON, BIANCA - University Of California, San Diego; MADARIS, KENDRA - The Ohio State University; CANOVA, TYLER - The Ohio State University; SIMS, CLARK - Arkansas Children'S Nutrition Research Center (ACNC); GOODYEAR, LAURIE - Harvard Medical School; ANDRES, ALINE - University Arkansas For Medical Sciences (UAMS); ZIOLO, MARK - The Ohio State University; BODE, LARS - University Of California, San Diego; STANFORD, KRISTIN - The Ohio State University

Submitted to: Nature Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/27/2020
Publication Date: 6/29/2020
Citation: Harris, J.E., Pinckard, K.M., Wright, K.R., Baer, L.A., Arts, P.J., Abay, E., Shettigar, V.K., Lehnig, A.C., Roberston, B., Madaris, K., Canova, T.J., Sims, C., Goodyear, L.J., Andres, A., Ziolo, M.T., Bode, L., Stanford, K.I. 2020. Exercise-induced 3'-sialyllactose in breast milk is a critical mediator to improve metabolic health and cardiac function in mice offspring. Nature Metabolism. https://doi.org/10.1038/s42255-020-0223-8.
DOI: https://doi.org/10.1038/s42255-020-0223-8

Interpretive Summary: The prevalence of obesity, type 2 diabetes, and cardiovascular disease is increasing in the United States and worldwide, and there is evidence that metabolic disease risk can be programmed early in life. Recent studies in animal models have shown that maternal exercise before and during pregnancy protects against offprings' development of impaired glucose metabolism, decreased cardiovascular function, and increased body fat (adiposity); however, the underlying mechanisms for maternal exercise to improve offspring health have not been identified. Here, we identify an exercise-induced increase in a component of human milk, known as 3'-siallylactose (3'SL), in humans and mice, and show that the beneficial effects of maternal exercise on offspring metabolic health and cardiac function are mediated in part by 3'SL. The results help form the scientific evidence base in support of policies and public health guidance to promote exercise in pregnant and breastfeeding mothers.

Technical Abstract: Poor maternal environments, such as under-or overnutrition, can increase the risk for the development of obesity, type 2 diabetes and cardiovascular disease in offspring. Recent studies in animal models have shown that maternal exercise before and during pregnancy abolishes the age-related development of impaired glucose metabolism, decreased cardiovascular function and increased adiposity; however, the underlying mechanisms for maternal exercise to improve offspring's health have not been identified. In the present study, we identify an exercise-induced increase in the oligosaccharide 3'-sialyllactose (3'-SL) in milk in humans and mice, and show that the beneficial effects of maternal exercise on mouse offspring's metabolic health and cardiac function are mediated by 3'-SL. In global 3'-SL knockout mice (3'-SL-/-), maternal exercise training failed to improve offspring metabolic health or cardiac function in mice. There was no beneficial effect of maternal exercise on wild-type offspring who consumed milk from exercise-trained 3'-SL-/- dams, whereas supplementing 3'-SL during lactation to wild-type mice improved metabolic health and cardiac function in offspring during adulthood. Importantly, supplementation of 3'-SL negated the detrimental effects of a high-fat diet on body composition and metabolism. The present study reveals a critical role for the oligosaccharide 3'-SL in milk to mediate the effects of maternal exercise on offspring's health. 3'-SL supplementation is a potential therapeutic approach to combat the development of obesity, type 2 diabetes and cardiovascular disease.