Friedman o&p2013

Editor's Notes

• #6: But how to tease apart question of genes vs. gestational exposure vs. post-natal environment?????
• #8: And this brings us to the concept of fetal programming. Morphological – that is the gross structure of tissues, and molecular – subcellular changes at the level of gene expression. It’s known from both human and animal data that an “adverse” environment can predispose the infant to later chronic disease.
• #14: When obesity and pregnancy combine, these metabolic changes can be exacerbated, creating a sort of perfect storm in terms of fuel exposure to the fetus. Importantly, we are not talking about diabetic pregnancy here, so while glucose may still play a role, we are focusing on other factors such as increased lipid mobilization and inflammatory cytokines. There is good evidence for later childhood disease, but there is less evidence as to why.
• #31: WE chose G130 because, as I have shown, it is a critical period for hypothalamic development. It is also a critical period for the development of other metabolic systems in peripheral organs like the pancrease
• #40: For those not familiar with the first & most important formed in primate development – this is a schematic of a human placenta. The placenta is the endocrine organ responsible for nutrient exchange and thus a key determinant of fetal growthn Abnormalities in placentation have been associated with emecvery obstetric complication. Despite this fact, the mechanismsr regulating placental growth / function are poorly understood. From implantation, the uterine vasculature undergoes significant angiogenesis intended to create a low resistance unit capable of maximizing nutrieant exchange. In this schematic….
• #43: We have previously reported that G130 fetuses have increased circulating cytokines as shown here. The cytokines with a statistically significant increase are highlighted in yellow.   This fetal inflammatory response is independent of maternal obesity. Is this systemic inflammatory response secondary to maternal inflammation?
• #46: Our study design is as follows- Offspring were used from mothers fed the control (blue) or HFD (red) . The offspring were exposed to the maternal diet throughout fetal life, from conception to birth, and during the nursing period until weaning at 8 mos of age. After weaning, offspring were placed on a control diet, allowing us to test if diet-reversal in HFD improved metabolic outcomes. Other groups of CON and HFD offspring were also exposed to a post-weaning HFD to test if metabolic outcomes are more severe. These groups will be shown with white shading. Studies have been ongoing for 3 years and final 4 th cohort of offspring will be studied this summer. Numerous measurements and data have been collected on these animals. Measurements of interest for today’s talk include bwt and dexa at 12 mos of age. These animals were sacrificed at 14 mos of age and plasma has analyzed for hormones and metabolites; liver tissue was collected for gene expression, protein expression, and lipid analysis. We also isolated hepatocytes and kupffer cells from a small subset of animals to perform more mechanistic in vitro studies.
• #49: Next, we took a closer look at the composition of FA in TG fraction using Mass Spec. We found a trend for increased TG in maternal HFD on postwean HFD compared CTR-HFD suggesting a programmed effect and is consistent with our fetal data. However, we also found high levels of TG in offspring on postwean CTR. This analysis has been initially performed in a small subset of samples and addition of more samples is planned. Most interestingly, we found increased N6:N3 in CON offsping on postweaning HFD and an even greater increase in offspring exposed to maternal and postweaning HFD. These data suggest increased exposure to potentially inflammatory FA.
• #59: We will study a total of 35 infants born to both obese and lean mothers. We will exclude… Infants will be studied at a single visit between 1-3 weeks of age. We will obtain the magnetic resonance studies described, a Pea Pod measurement, which is a standard instrument for measuring total body adiposity, skinfold measurements to see if easily obtained anthropometric measures correlate with our MR measures, and a feeding questionnaire to assess for differences between bottle fed and breastfed infants.
• #62: We will use magnetic resonance spectroscopy to quantify liver fat. MRS is the most sensitive radiographic technique for measuring liver fat, and its validity has been established in comparisons to liver biopsy triglyceride measurements. MRS is based on the fac that each molecule has its own resonance signature within the magnetic field. This square is called the voxel, and it is placed in the area of interest, and you then are given the signatures of molecules in that volume of tissue. The area under the curve then represents the abundance of that particular molecule. On the left is a spectroscopic graph with limited liver fat, as demonstrated in the right sided peak compared to the water peak. On the right is an example of a spectroscopic measure of increased liver fat.
• #65: To try to condense this talk into a punch line…..
• #66: One way of answering why this happens, is to modify the environment. So we want to reduce inflammation, IR, and lipids…. Clinician are understandably hesistant to use drugs on patients whose obesity is not overtly pathological Focusing in on dietary modifications – what can we modify?
• #67: In the context of pregnancy, treatment is focused on proper delivery to the fetus for brain development….. Concern has been raised about improper transport in context of obese pregnancy, but the focus has more been on increasing fetal levels vs. utilization as a maternal treatment.