OR02-4 Maternal resveratrol supplementation reverses fetal hepatic lipid accumulation during maternal high fat diet exposure in non-human primate: Effect on mitochondrial activity and stress signals

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR02-Diabetes in Pregnancy
Translational
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:15 PM
Room 303 (Moscone Center)
Stephanie R Thorn*1, Sean A Newsom1, Rachel C Janssen1, Rebecca M Aikens1, Karalee C Baquero2, Diana Lynn Takahashi2, Kevin L Grove2 and Jed Friedman1
1University of Colorado Anschutz Medical Campus, Aurora, CO, 2Oregon Health and Science University/ONPRC, Beaverton, OR
Maternal obesity or high fat (HF) diet consumption produces adverse metabolic outcomes in the offspring.  To study the mechanisms involved, we have used a non-human primate (Japanese macaques) model where mothers are fed a HF diet beginning at 3 yr of age and continuing through their subsequent pregnancies.  Previously, we reported that maternal HF diet during pregnancy results in increased lipid accumulation, oxidative stress, and apoptosis in the fetal liver.   Here, we tested whether maternal resveratrol supplementation, a potent anti-oxidant, would ameliorate the harmful effects of maternal HF diet on the developing fetal liver.  HF diet mothers received resveratrol (HF+RESV, 0.37% diet) throughout pregnancy.  Fetuses were studied in early third trimester by c-section from maternal HF+RESV (n=7), HF (n=18), and CON (n=14) groups.  Liver TG content was 3-fold higher in HF compared to CON fetuses and was reduced in HF+RESV fetuses to concentrations similar to CON fetuses.  Hepatic citrate synthase activity, a marker of mitochondria number, was decreased by ~10% (P<0.05) in HF and HF+RESV (P=0.06) compared to CON fetuses and correlated with hepatic triglyceride content (r= -0.42, P<0.005).  Protein expression of SIRT3, a key regulator of mitochondria acetylation and function, was decreased in HF compared to CON and HF+RESV fetal livers and correlated with fetal liver TG accumulation (r= -0.47, P<0.01), citrate synthase activity (r= 0.61, P<0.005) and expression of the anti-oxidant MnSOD (r= -0.76, P<0.001).  Interestingly, protein expression of MnSOD and phosphorylation of EIF2α, JNK, and NFKB (markers of cell stress and inflammation) were increased in HF fetal liver and remained higher in HF+RESV compared to CON fetal livers.  SIRT1 protein expression, a target of resveratrol, was increased by ~15% in HF+RESV compared to CON fetal livers and circulating resveratrol concentrations were elevated in HF+RESV compared to CON maternal and fetal plasma (maternal: 0.499 ± 0.36 vs 0.131 ± 0.04 ng/ml; fetal: 0.749 ± 0.57 vs. 0.134 ± 0.02 ng/ml) indicative of placental transfer to the fetus.  These results indicate that maternal RESV supplementation during HF diet reduces fetal hepatic TG accumulation. The beneficial effects of RESV may be due to direct effects on the fetal liver or improved effects on maternal and placental metabolism.   Several stress related proteins remained activated in HF+RESV liver, suggesting that increased lipid supply or maternal or placental derived inflammatory signals during maternal HF diet exposure remain capable of activating these pathways in the fetal liver despite lower triglyceride content.  Consequently, maternal RESV supplementation may be an important intervention to improve fetal outcomes during maternal HF diet exposure.

Nothing to Disclose: SRT, SAN, RCJ, RMA, KCB, DLT, KLG, JF

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH-K01-DK090199 awarded to SRT; NIH-R24-DK090964 awarded to KLG and JEF