|Shankar, Kartik -|
|Kang, Ping -|
|Harrell, Amanda -|
|Zhong, Ying -|
|Marecki, John -|
|Ronis, Martin -|
Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 11, 2010
Publication Date: April 6, 2010
Citation: Shankar, K., Kang, P., Harrell, A., Zhong, Y., Marecki, J.C., Ronis, M.J., Badger, T.M. 2010. Maternal overweight programs insulin and adiponectin signaling in the offspring. Endocrinology. 151(6):2577-2589. Interpretive Summary: Maternal body composition at conception has long-term consequences for the health of the offspring. We have studied whether in utero exposure to maternal obesity increases the risk of obesity in the offspring in later-life using a model of obesity in the rat. Using this model we have demonstrated that maternal obesity via metabolic factors independent of genetic influences leads to increased risk of obesity in the offspring when challenged with a high fat diet. In the present studies we investigated changes in expression of genes in the liver of offspring at weaning prior to development of obesity. Using microarrays we identified expression of 147 transcripts to be altered in the offspring of overweight dams. Of these, genes involved in production of fat regulated via the factor, SREBP-1 were significantly up-regulated. In addition, the serum levels of the hormones adiponectin and FGF21 were down-regulated. Since, these hormones are involved in increasing insulin sensitivity and energy expenditure, our findings suggest that maternal obesity may program the responsiveness in the offspring of overweight dams and hence may increase susceptibility to weight gain and obesity.
Technical Abstract: Gestational exposure to maternal overweight (OW) influences the risk of obesity in adult-life. Male offspring from OW dams gain greater body weight, fat mass and develop insulin resistance when fed high fat diets (45 percent fat). In this report we identify molecular targets of maternal OW-induced programming at postnatal day 21 (PND21), prior to challenge with HFD. We conducted global transcriptomic profiling, gene/protein expression analyses and characterization of downstream signaling of insulin and adiponectin pathways, in conjunction with endocrine and biochemical characterization. Offspring born to OW dams displayed increased serum insulin, leptin and resistin levels (p less than 0.05) at PND21 preceding changes in body composition. A lipogenic transcriptomic signature in the liver, prior to development of obesity was evident in OW-dam offspring. A coordinated locus of 20 SREBP-1 regulated target genes was induced by maternal OW. Increased nuclear levels of SREBP-1 and recruitment to the FASN promoter were confirmed via ELISA and ChIP analyses, respectively. Higher FASN and ACC protein and pAKT (Thr308) and p-IR-beta were confirmed via immunoblotting. Maternal OW also attenuated AMP-kinase/ PPAR-alpha signaling in the offspring liver, including transcriptional down-regulation of several PPAR-alpha regulated genes. Hepatic mRNA and circulating FGF21 levels were significantly lower in OW-dam offspring. Further, serum levels of HMW adiponectin (p less than 0.05) were decreased in OW dam offspring. Phosphorylation of hepatic AMP-kinase (Thr172) was significantly decreased in OW dam offspring, along with lower AdipoR1 mRNA. Our results strongly suggest that gestational exposure to maternal obesity programs multiple aspects of energy-balance regulation in the offspring.