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Title: Chronic maternal low-protein diet in mice affects anxiety, night-time energy expenditure and sleep patterns, but not circadian rhythm in male offspring

item CROSSLAND, RANDY - Baylor College Of Medicine
item BALASA, ALFRED - Baylor College Of Medicine
item RAMAKRISHNANA, RAJESH - Baylor College Of Medicine
item MAHADEVAN, SANGEETHA - Baylor College Of Medicine
item FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC)
item VAN DEN VEYVER, IGNATIA - Baylor College Of Medicine

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/1/2016
Publication Date: 1/18/2017
Citation: Crossland, R.F., Balasa, A., Ramakrishnana, R., Mahadevan, S.K., Fiorotto, M.L., Van Den Veyver, I.B. 2017. Chronic maternal low-protein diet in mice affects anxiety, night-time energy expenditure and sleep patterns, but not circadian rhythm in male offspring. PLoS One. 12(1):e0170127.

Interpretive Summary: Adverse exposures, such as suboptimal nutrition during fetal and neonatal life, can have long-term consequences for an individual's health and well-being. Yet, details of which types of exposures, their timing and the mechanisms by which they affect the offspring's health are still not fully understood. In this study it was demonstrated that male offspring of rat dams that had been fed chronically on a low-protein diet from four weeks prior to pregnancy and throughout gestation and lactation, were significantly smaller, had higher body fat, were less active at night and had lower levels of energy, even though they had all been fed a normal diet from weaning. Although the offspring were less active at night, they showed no circadian rhythm alterations, but demonstrated mild anxiety-related behavioral differences. These results highlight the importance of maternal diet during pregnancy and lactation for the long term health of the offspring.

Technical Abstract: Offspring of murine dams chronically fed a protein-restricted diet have an increased risk for metabolic and neurobehavioral disorders. Previously we showed that adult offspring, developmentally exposed to a chronic maternal low-protein (MLP) diet, had lower body and hind-leg muscle weights and decreased liver enzyme serum levels. We conducted energy expenditure, neurobehavioral and circadian rhythm assays in male offspring to examine mechanisms for the body-weight phenotype and assess neurodevelopmental implications of MLP exposure. C57BL/6J dams were fed a protein restricted (8% protein, MLP) or a control protein (20% protein, C) diet from four weeks before mating until weaning of offspring. Male offspring were weaned to standard rodent diet (20% protein) and single-housed until 8-12 weeks of age. We examined body composition, food intake, energy expenditure, spontaneous rearing activity and sleep patterns and performed behavioral assays for anxiety (open field activity, elevated plus maze [EPM], light/dark exploration), depression (tail suspension and forced swim test), sociability (three-chamber), repetitive (marble burying), learning and memory (fear conditioning), and circadian behavior (wheel-running activity during light-dark and constant dark cycles). We also measured circadian gene expression in hypothalamus and liver at different Zeitgeber times (ZT). Male offspring from separate MLP exposed dams had significantly greater body fat (P = 0.03), less energy expenditure (P = 0.004), less rearing activity (P = 0.04) and a greater number of night-time rest/sleep bouts (P = 0.03) compared to control. MLP offspring displayed greater anxiety-like behavior in the EPM (P<0.01) but had no learning and memory deficit in fear-conditioning assay (P = 0.02). There was an effect of time on Per 1, Per 2 and Clock circadian gene expression in the hypothalamus but not on circadian behavior. Thus, transplacental and early developmental exposure of dams to chronic MLP reduces food intake and energy expenditure, increases anxiety like behavior and disturbs sleep patterns but not circadian rhythm in adult male offspring.