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Title: High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring

item BORENGASSER, SARAH - Arkansas Children'S Nutrition Research Center (ACNC)
item KANG, PING - Arkansas Children'S Nutrition Research Center (ACNC)
item FASKE, JENNIFER - Arkansas Children'S Nutrition Research Center (ACNC)
item GOMEZ-ACEVEDO, HORACIO - Arkansas Children'S Nutrition Research Center (ACNC)
item BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)
item Badger, Thomas
item SHANKAR, KARTIK - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/21/2013
Publication Date: 1/9/2014
Citation: Borengasser, S.J., Kang, P., Faske, J., Gomez-Acevedo, H., Blackburn, M.L., Badger, T.M., Shankar, K. 2014. High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring. PLoS One. 9(1):e84209. doi:10.1371/journal.pone.0084209.

Interpretive Summary: Exposure to gestational obesity negatively impacts offspring and initiates a vicious cycle of obesity. In fact, offspring of obese rats develop obesity-associated diseases such as insulin resistance, nonalcoholic fatty liver disease, and cardiovascular disease. At weaning, offspring of obese rats have altered gene expression patterns that increase the susceptibility for obesity despite the absence of obesity at this early age, suggesting changes in gene expression may precede the development of obesity. Here we present findings that offspring who were exposed to maternal obesity in utero, and were fed a high fat diet post weaning for two weeks, had altered circadian rhythms. Circadian rhythm is known to be tightly coupled to metabolism and regulated by exposure to light, feeding schedule, type of food, sleep, and physical activity. We found that key circadian and metabolic targets were impaired by the combination of maternal obesity and post-weaning high fat diet. Specifically, a key target that is considered both a circadian and metabolic regulator, called PPAR alpha, had decreased gene expression in obese dam offspring fed high fat diet. Mathematical modeling revealed that the PPAR alpha gene expression was altered by decreased rates of mRNA synthesis and increased rates of mRNA degradation. In addition, epigenetic influence via histone modifications on the PPAR alpha promoter, a region that controls gene transcription, was found to be modified to decrease gene expression by decreased activation and increased gene silencing in offspring of obese dams fed high fat diet. In summary, exposure to maternal obesity appears to "poise" offspring to be hyper-responsive to HFD promoting the development of obesity in later life.

Technical Abstract: The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosis, and lipogenic gene expression in the liver at weaning. However, the precise underlying mechanisms leading to metabolic dysregulation in the offspring remains unclear. Using a rat model of overfeeding-induced obesity, we previously demonstrated that exposure to maternal obesity from conception to birth is sufficient to program increased obesity risk in the offspring. Offspring of obese rat dams gain greater body weight and fat mass when fed high fat diet (HFD) as compared to lean dam counterparts. Since disruptions of diurnal circadian rhythm are known to detrimentally impact metabolically active tissues such as liver, we examined the hypothesis that maternal obesity leads to perturbations of core clock components and thus energy metabolism in offspring liver. Offspring from lean and obese dams were examined at post-natal day 35, following a short (2-wk) HFD challenge. Hepatic mRNA expression of circadian (CLOCK, BMAL1, REV-ERBa, CRY, PER) and metabolic (PPARa, SIRT1) genes were strongly suppressed in offspring exposed to both maternal obesity and HFD. Using a mathematical model, we identified two distinct biological mechanisms that modulate PPAR alpha mRNA expression: i) decreased mRNA synthesis rates; and ii) increased non-specific mRNA degradation rate. Moreover, our findings demonstrate that changes in PPAR alpha transcription were associated with epigenomic alterations in H3K4me3 and H3K27me3 histone marks near the PPAR alpha transcription start site. Our findings indicated that offspring from obese rat dams have detrimental alternations to circadian machinery that may contribute to impaired liver metabolism in response to HFD, specifically via reduced PPARa expression prior to obesity development.