|Borengaser, Sarah -|
|Zhong, Ying -|
|Kang, Ping -|
|Lindsey, Forrest -|
|Ronis, Martin -|
|Gomez-Acevedo, Horacio -|
|Shankar, Kartik -|
Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 5, 2013
Publication Date: November 1, 2013
Citation: Borengaser, S., Zhong, Y., Kang, P., Lindsey, F., Ronis, M.J., Badger, T.M., Gomez-Acevedo, H., Shankar, K. 2013. Maternal obesity enhances white adipose tissue differentiation and alters genome-scale DNA methylation in male rat offspring. Endocrinology. 154(11):4113-4125. Interpretive Summary: Children born to obese moms have an increased risk to become obese as adults as compared to children born to lean moms. In this study we examined the white adipose tissue (fat) from offspring of lean and obese rat dams (fat is the primary storage site for excess energy) to better understand the susceptibility to obesity. One set of female rats was overfed a liquid diet by infusion for 3 weeks to make the rats obese. Offspring exposure to obesity was limited to pregnancy as surrogate lean dams were used during lactation. At weaning, offspring of lean and obese rat dams were sacrificed and fat was collected for analysis. Gene and protein expression of key pathways involved in the expansion of adipose tissue were examined. It appears that white adipose tissue from offspring of obese dams are primed to expand by synthesizing more fat (lipogenesis) and by committing more cells to become fat (adipogenesis). Not only did this study show alternations in various lipogenic and adipogenic genes by various analyses, but we also found changes in DNA methylation of pro-adipogenic factors. DNA methylation is an epigenetic change that can be passed to offspring from parents as a result of environmental changes and can alter gene expression. Our findings strongly suggest that offspring exposed to maternal obesity have an increased propensity to become obese via an epigenetic mechanism.
Technical Abstract: The risk of obesity in adulthood is strongly influenced by maternal body composition. Here we examined the hypothesis that maternal obesity influences white adipose tissue (WAT) transcriptome and increases propensity for adipogenesis in the offspring, prior to the development of obesity, using an established model of long-term metabolic programming. Employing an overfeeding-based rat model, where exposure to obesity is limited to preconception and gestation alone, we conducted: global transcriptomic profiling in WAT, gene/protein expression analysis of lipogenic and adipogenic pathways, and examined adipogenic differentiation of WAT SV cells ex vivo. Using reduced representation bisulfite sequencing (RRBS), we also evaluated genome-scale changes in DNA methylation in offspring WAT. Maternal obesity led to extensive changes in expression of genes (+/- 1.8-fold, P = 0.05), revealing a distinct up-regulation of lipogenic pathways in WAT. mRNA expression of a battery of SREBP-1 regulated genes was increased in OB-dam offspring, which were confirmed by immunoblotting. In conjunction with lipogenic gene expression, obese dam offspring showed increased GLUT-4 mRNA/protein expression and greater AKT phosphorlyation following acute insulin challenge, suggesting sensitization of insulin signaling in WAT. Offspring of obese dams also exhibited increased in vivo expression of adipogenic regulators(PPAR-gamma, C/EBP-a and C/EBP-beta), associated with greater ex vivo differentiation of WAT SV cells. These transcriptomic changes were associated with alterations in DNA methylation of CpG sites and CGI-shores, proximal to developmentally important genes, including key pro-adipogenic factors (Zfp423 and C/EBP-beta). Our findings strongly suggest that the maternal obesity in utero alters adipocyte commitment and differentiation via epigenetic mechanisms.