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Title: Early postnatal nutrition determines adult physical activity and energy expenditure in female mice

Author
item Li, Ge - Children'S Nutrition Research Center (CNRC)
item Kohorst, John - Children'S Nutrition Research Center (CNRC)
item Zhang, Wenjuan - Children'S Nutrition Research Center (CNRC)
item Laritsky, Eleonora - Children'S Nutrition Research Center (CNRC)
item Kunde-ramamoorthy, Govindarajan - Children'S Nutrition Research Center (CNRC)
item Baker, Maria - Children'S Nutrition Research Center (CNRC)
item Fiorotto, Marta - Children'S Nutrition Research Center (CNRC)
item Waterland, Robert - Children'S Nutrition Research Center (CNRC)

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/21/2013
Publication Date: 4/1/2013
Citation: Li, G., Kohorst, J.J., Zhang, W., Laritsky, E., Kunde-Ramamoorthy, G., Baker, M.S., Fiorotto, M.L., Waterland, R.A. 2013. Early postnatal nutrition determines adult physical activity and energy expenditure in female mice. Diabetes. 62:2773-2783.

Interpretive Summary: We are interested in understanding how overnutrition (too much food) during certain "critical" periods of development leads to permanent changes in body weight regulation and, therefore, risk of obesity. We studied a classic model of early postnatal overnutrition: the suckling-period small litter model, in the mouse. Essentially, several litters of mice born on the same day are pooled, then fostered back to mothers in either normal size (9 pups/litter, control) or small litters (4 pups/litter); small litter pups get more milk than pups in normal size litters. Although all mice are weaned onto the same diet, the small litter offspring remain heavier and fatter throughout life. We measured food intake, energy expenditure, physical activity, and hypothalamic DNA methylation and gene expression in a large number of control and small litter mice. We found that, particularly in female offspring, early postnatal overnutrition causes reduced physical activity in adulthood, and this is correlated with persistent changes in hypothalamic DNA methylation. Our data provide important insights into "developmental programming" of obesity.

Technical Abstract: Decades of research in rodent models has shown that early postnatal overnutrition induces excess adiposity and other components of metabolic syndrome that persist into adulthood. The specific biologic mechanisms explaining the persistence of these effects, however, remain unknown. On postnatal day 1 (P1), mice were fostered in control (C) or small litters (SL). SL mice had increased body weight and adiposity at weaning (P21) which persisted to adulthood (P180). Detailed metabolic studies indicated that female adult SL mice have decreased physical activity and energy expenditure, but not increased food intake. Genome-scale DNA methylation profiling identified extensive changes in hypothalamic DNA methylation during the suckling period, suggesting it is a critical period for developmental epigenetics in the mouse hypothalamus. Indeed, SL mice exhibited subtle and sex-specific changes in hypothalamic DNA methylation that persisted from early life to adulthood, providing a potential mechanistic basis for the sustained physiological effects. Expression profiling in adult hypothalamus likewise provided evidence of widespread sex-specific alterations in gene expression. Together, our data indicate that early postnatal overnutrition leads to a reduction in spontaneous physical activity and energy expenditure in females, and suggest that early postnatal life is a critical period during which nutrition can affect hypothalamic developmental epigenetics.