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192: Adipose tissue dysfunction in a model of developmental programming of metabolic syndrome
www.AJOG.org
Clinical Obstetrics, Medical-Surgical-Disease, Neonatology, Physiology-Endocrinology
191 Changes in visceral adiposity and liver fat in the offspring in a mouse model of pre-pregnancy obesity: a longitudinal study using computed tomography
Poster Session I
192 Adipose tissue dysfunction in a model of developmental programming of metabolic syndrome Egle Bytautiene1, Debdeep Banerjee1, Talar Kechichian1, Huaizhi Yin1, Elena Sbrana1, Esther Tamayo1, Nicola Abate2, George R. Saade1
Egle Bytautiene1, Nicola Abate2, Kathleen Vincent1, Igor Patrikeev3, Jingna Wei3, Massoud Motamedi3, George Saade1 1 The University of Texas Medical Branch, Obstetrics & Gynecology, Galveston, TX, 2The University of Texas Medical Branch, Internal Medicine, Galveston, TX, 3The University of Texas Medical Branch, Center for Biomedical Engineering, Galveston, TX
1 The University of Texas Medical Branch, Obstetrics & Gynecology, Galveston, TX, 2The University of Texas Medical Branch, Internal Medicine, Galveston, TX
OBJECTIVE: The epidemiology of the fetal origin of adult diseases, including obesity, diabetes, and hypertension, has been well established but the mechanisms remain to be determined. The objective of this study was to evaluate the sequence of change in postnatal visceral adiposity and fatty liver infiltration using a previously validated mouse model of developmental programming of metabolic syndrome (MetS) induced by maternal pre-pregnancy obesity. STUDY DESIGN: CD-1 female mice were placed on standard (SF) or high fat diet (HF) starting 3 months before mating. After weaning, their offspring were placed on SF diet. The offspring (males: SF n⫽7, HF n⫽8; females: SF n⫽9, HF n⫽7) were weighed and imaged using a micro-computed tomography (CT) scanner monthly from 1 until 6 months of age. CT images were used to longitudinally evaluate visceral adipose tissue (VAT), measured as percent VAT area to total body area at the L5 vertebrae level, and fat infiltration in the liver, measured as the ratio of spleen/liver radiodensity. Data were analyzed by maternal diet and gender using 2-way ANOVA (significance: P⬍0.05). RESULTS: There were no significant differences in either male or female total body weights between SF and HF groups until 6 months of age when the HF offspring became heavier (P⬍0.05 in both genders). Significantly higher VAT was seen in both genders in the HF compared to SF group starting at 3 months of age (Figure, females P⬍0.05 at 3, 5, 6 months, and P⬍0.01 at 4 months, males P⬍0.001 3 thru 6 months). Significant fat infiltration into the liver was detected in HF female offspring starting at 4 month of age (P⬍0.01 at 4, P⬍0.05 at 5, and P⬍0.001 at 6 months) and in HF males offspring starting at 3 months (P⬍0.05 at 3 and 6, P⬍0.001 at 4, and P⬍0.01 at 6 months). CONCLUSION: Abnormal visceral adiposity and fatty liver infiltration occur prior to any change in body weight in this animal model of developmental programming of MetS. This non-invasive approach may assist in early detection of offspring at risk of MetS, and application of postnatal age-specific interventions to prevent its long term consequences.
OBJECTIVE: Obesity is characterized by adipose tissue accumulation, which in turn is associated with metabolic consequences. Distribution, type, and function of adipose tissue accumulation are believed to be more important than overall change in body or fat mass. The objective of this study was to investigate whether visceral adipose tissue dysfunction is present in a previously validated mouse model of developmental programming of metabolic syndrome. STUDY DESIGN: CD-1 female mice were placed on standard (SF) or high fat (HF) diet starting 3 months before mating, and continued during pregnancy and weaning. The offspring were placed on SF diet after weaning. At 6 months of age, the offspring were euthanized and tissues collected. mRNA expression of hypoxia-inducible factor 1␣ (HIF-1␣)and transforming growth factor 3 (TGF3), and protein expressions of angiotensin (ANG) and its receptors, angiotensin receptor 1 and 2 (AT1 and AT2, respectively), in adipose tissue and kidney were determined using quantitative real time RT-PCR and Western blot (SF n⫽10-14, HF n⫽8-10). Results were analyzed using Students t-test (significance: P⬍0.05). RESULTS: HIF-1␣ mRNA expression was significantly increased in adipose tisssue from HF offspring compared to SF group (P⫽0.04), with no significant differences in TGF3 mRNA expression. ANG protein expression was significantly higher and AT2 was significantly lower in adipose tissue from offspring born to HF mothers as compared to SF group (Figure). There were no significant differences in the expression of HIF-1␣;, TGF3, ANG, AT1 and AT2 in the kidneys between the 2 offspring groups. CONCLUSION: Maternal pre-pregnancy obesity from high fat diet predisposes the offspring for adipose tissue dysfunction later in life. The altered adipose tissue function can then lead to a number of cascade events involved in the developmental origin of adult hypertension and metabolic syndrome.
Supplement to JANUARY 2012 American Journal of Obstetrics & Gynecology
S97
Poster Session I
Clinical Obstetrics, Medical-Surgical-Disease, Neonatology, Physiology-Endocrinology
www.AJOG.org
194 The impact of maternal weight upon the effectiveness of 17-hydroxyprogesterone in preventing preterm birth among twin gestations Erica Heitmann1, George Lu2, C. Andrew Combs3, Thomas J. Garite3, Kimberly Maurel4, For the Obstetrix Collaborative Research Network3 1 University of Missouri, Kansas City, Department of Obstetrics and Gynecology, Kansas City, MO, 2Obstetrix Medical Group of Kansas and Missouri, Center for Research, Education, & Quality, Kansas City, MO, 3 Obstetrix Medical Group, Center for Research, Education, & Quality, Sunrise, FL, 4Obstetrix Medical Group twins trial
193 Maternal glucose response to betamethasone administration Elizabeth Langen1, Jessica Lewis2, Joyce Sung1, Mark Taslimi1, James Byrne3, Yasser El-Sayed1 1 Stanford University School of Medicine/Lucile Salter Packard Children’s Hospital, Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, Stanford, CA, 2Stanford University School of Medicine/Lucile Salter Packard Children’s Hospital, Stanford Univeristy School of Medicine, Stanford, CA, 3Santa Clara Valley Medical Center, Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, San Jose, CA
OBJECTIVE: To describe the pattern of maternal glucose response to betamethasone administration using a continuous glucose monitoring system. STUDY DESIGN: A prospective observational trial was conducted among women receiving clinically indicated betamethasone between 24 and 34 weeks of pregnancy. Patients received two doses of 12 mg of betamethasone intramuscularly 24 hours apart. At the time of initial betamethasone administration, a Dexcom continuous glucose monitoring system was inserted which monitored tissue glucose levels every five minutes. Glucose levels were monitored for 7 days or until hospital discharge, whichever came first. We recorded the percentage of time women spent above three glucose thresholds: 110, 144, and 180 mg/dL. These thresholds were chosen as they have been associated with neonatal hypoglycemia in women in labor. Additionally, a comparison was made to a cohort of non-diabetic women of similar gestational ages who did not receive betamethasone. RESULTS: Seventeen women were enrolled at the time of betamethasone administration and data were available for 15 patients. There were 11 non-diabetic and 4 diabetic women. Five additional nondiabetic women who did not receive betamethasone served as controls. The average gestational age at enrollment was 29 2/7wk (range 25 1/7-34wk). Both diabetic and non-diabetic women had the highest recorded blood glucose readings between 24- 48 hours after the first injection of betamethasone. In that period, non-diabetic women spent 73%, 40%, and 17% of the time with blood glucose levels above the 110, 144, and 180 mg/dL thresholds, respectively. During a 24 hour monitoring period, non-diabetic women not receiving betamethasone spent 27%, 9%, and 0.2% above the same thresholds. At each glucose threshold, the difference between non-diabetics who did and did not receive betamethasone was statistically significant (P⫽0.003, P⫽0.03, P⫽0.01 respectively). CONCLUSION: Diabetic women receiving bethamethasone manifest significant hyperglycemia after betamethasone administration. This may need to be taken into account if delivery is imminent.
S98
OBJECTIVE: To evaluate the impact of maternal weight on the efficacy of 17-hydroxyprogesterone caproate (17P) for the prevention of preterm birth (PTB) in twin gestations and reduction of composite neonatal morbidity (CNM). We hypothesized that 17P would be more effective in non-obese women because a prior pharmacokinetic study had demonstrated a significant impact of maternal BMI upon 17P serum concentrations. STUDY DESIGN: A secondary analysis was performed on data from the Obstetrix trial of 17P in twins. 234 patients had recorded maternal weight and were included in the analysis. Pre-pregnancy maternal weight was calculated as quartiles (Q): Q1⫽97-133 pounds; Q2⫽133150 pounds; Q3⫽150-176 pounds; and Q4⫽176-332 pounds. PTB was defined as 2 categories: ⬍34 weeks and 34.0-36.9 weeks. Rates of PTB and CNM were calculated in each quartile for both the 17 P and placebo groups using the Fishers exact test. RESULTS: The rate of PTB .05). The rates of PTB .05). When BMI was used, the rate of PTB .05). When BMI was examined for PTB .05). Survival analysis showed that 17P did not significantly prolong pregnancy compared to placebo in any tercile of weight or BMI. CONCLUSION: 17P is not more effective in preventing PTB in lower weight categories, regardless of the definition used. This suggests that maternal weight does not explain the failure of 17P to prolong pregnancy in twins.
195 Differential expression of tunica internal endothelial cell kinase in the center and periphery of normal and growth restricted placentas Erica Heitmann1, Paul Singh1, Alok De1, Devika Maulik1, David Mundy1, Dev Maulik1 1 University of Missouri, Kansas City, Department of Obstetrics and Gynecology, Kansas City, MO
OBJECTIVE: Aberrant placental angiogenesis has a role in fetal growth restriction (FGR). Angiogenic factors have been found to differ between the center and periphery of normal placentas. Tunica Internal Endothelial Cell Kinase (Tie2) is an endothelial cell-specific receptor tyrosine kinase, whose activation is positively and negatively modulated by angiopoietin family. Angiopoietin-mediated modulation of Tie2 activation contributes to normal blood vessel development, maturation, maintenance, remodeling and stability. We have previously
American Journal of Obstetrics & Gynecology Supplement to JANUARY 2012
Clinical Obstetrics, Medical-Surgical-Disease, Neonatology, Physiology-Endocrinology
191 Changes in visceral adiposity and liver fat in the offspring in a mouse model of pre-pregnancy obesity: a longitudinal study using computed tomography
Poster Session I
192 Adipose tissue dysfunction in a model of developmental programming of metabolic syndrome Egle Bytautiene1, Debdeep Banerjee1, Talar Kechichian1, Huaizhi Yin1, Elena Sbrana1, Esther Tamayo1, Nicola Abate2, George R. Saade1
Egle Bytautiene1, Nicola Abate2, Kathleen Vincent1, Igor Patrikeev3, Jingna Wei3, Massoud Motamedi3, George Saade1 1 The University of Texas Medical Branch, Obstetrics & Gynecology, Galveston, TX, 2The University of Texas Medical Branch, Internal Medicine, Galveston, TX, 3The University of Texas Medical Branch, Center for Biomedical Engineering, Galveston, TX
1 The University of Texas Medical Branch, Obstetrics & Gynecology, Galveston, TX, 2The University of Texas Medical Branch, Internal Medicine, Galveston, TX
OBJECTIVE: The epidemiology of the fetal origin of adult diseases, including obesity, diabetes, and hypertension, has been well established but the mechanisms remain to be determined. The objective of this study was to evaluate the sequence of change in postnatal visceral adiposity and fatty liver infiltration using a previously validated mouse model of developmental programming of metabolic syndrome (MetS) induced by maternal pre-pregnancy obesity. STUDY DESIGN: CD-1 female mice were placed on standard (SF) or high fat diet (HF) starting 3 months before mating. After weaning, their offspring were placed on SF diet. The offspring (males: SF n⫽7, HF n⫽8; females: SF n⫽9, HF n⫽7) were weighed and imaged using a micro-computed tomography (CT) scanner monthly from 1 until 6 months of age. CT images were used to longitudinally evaluate visceral adipose tissue (VAT), measured as percent VAT area to total body area at the L5 vertebrae level, and fat infiltration in the liver, measured as the ratio of spleen/liver radiodensity. Data were analyzed by maternal diet and gender using 2-way ANOVA (significance: P⬍0.05). RESULTS: There were no significant differences in either male or female total body weights between SF and HF groups until 6 months of age when the HF offspring became heavier (P⬍0.05 in both genders). Significantly higher VAT was seen in both genders in the HF compared to SF group starting at 3 months of age (Figure, females P⬍0.05 at 3, 5, 6 months, and P⬍0.01 at 4 months, males P⬍0.001 3 thru 6 months). Significant fat infiltration into the liver was detected in HF female offspring starting at 4 month of age (P⬍0.01 at 4, P⬍0.05 at 5, and P⬍0.001 at 6 months) and in HF males offspring starting at 3 months (P⬍0.05 at 3 and 6, P⬍0.001 at 4, and P⬍0.01 at 6 months). CONCLUSION: Abnormal visceral adiposity and fatty liver infiltration occur prior to any change in body weight in this animal model of developmental programming of MetS. This non-invasive approach may assist in early detection of offspring at risk of MetS, and application of postnatal age-specific interventions to prevent its long term consequences.
OBJECTIVE: Obesity is characterized by adipose tissue accumulation, which in turn is associated with metabolic consequences. Distribution, type, and function of adipose tissue accumulation are believed to be more important than overall change in body or fat mass. The objective of this study was to investigate whether visceral adipose tissue dysfunction is present in a previously validated mouse model of developmental programming of metabolic syndrome. STUDY DESIGN: CD-1 female mice were placed on standard (SF) or high fat (HF) diet starting 3 months before mating, and continued during pregnancy and weaning. The offspring were placed on SF diet after weaning. At 6 months of age, the offspring were euthanized and tissues collected. mRNA expression of hypoxia-inducible factor 1␣ (HIF-1␣)and transforming growth factor 3 (TGF3), and protein expressions of angiotensin (ANG) and its receptors, angiotensin receptor 1 and 2 (AT1 and AT2, respectively), in adipose tissue and kidney were determined using quantitative real time RT-PCR and Western blot (SF n⫽10-14, HF n⫽8-10). Results were analyzed using Students t-test (significance: P⬍0.05). RESULTS: HIF-1␣ mRNA expression was significantly increased in adipose tisssue from HF offspring compared to SF group (P⫽0.04), with no significant differences in TGF3 mRNA expression. ANG protein expression was significantly higher and AT2 was significantly lower in adipose tissue from offspring born to HF mothers as compared to SF group (Figure). There were no significant differences in the expression of HIF-1␣;, TGF3, ANG, AT1 and AT2 in the kidneys between the 2 offspring groups. CONCLUSION: Maternal pre-pregnancy obesity from high fat diet predisposes the offspring for adipose tissue dysfunction later in life. The altered adipose tissue function can then lead to a number of cascade events involved in the developmental origin of adult hypertension and metabolic syndrome.
Supplement to JANUARY 2012 American Journal of Obstetrics & Gynecology
S97
Poster Session I
Clinical Obstetrics, Medical-Surgical-Disease, Neonatology, Physiology-Endocrinology
www.AJOG.org
194 The impact of maternal weight upon the effectiveness of 17-hydroxyprogesterone in preventing preterm birth among twin gestations Erica Heitmann1, George Lu2, C. Andrew Combs3, Thomas J. Garite3, Kimberly Maurel4, For the Obstetrix Collaborative Research Network3 1 University of Missouri, Kansas City, Department of Obstetrics and Gynecology, Kansas City, MO, 2Obstetrix Medical Group of Kansas and Missouri, Center for Research, Education, & Quality, Kansas City, MO, 3 Obstetrix Medical Group, Center for Research, Education, & Quality, Sunrise, FL, 4Obstetrix Medical Group twins trial
193 Maternal glucose response to betamethasone administration Elizabeth Langen1, Jessica Lewis2, Joyce Sung1, Mark Taslimi1, James Byrne3, Yasser El-Sayed1 1 Stanford University School of Medicine/Lucile Salter Packard Children’s Hospital, Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, Stanford, CA, 2Stanford University School of Medicine/Lucile Salter Packard Children’s Hospital, Stanford Univeristy School of Medicine, Stanford, CA, 3Santa Clara Valley Medical Center, Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, San Jose, CA
OBJECTIVE: To describe the pattern of maternal glucose response to betamethasone administration using a continuous glucose monitoring system. STUDY DESIGN: A prospective observational trial was conducted among women receiving clinically indicated betamethasone between 24 and 34 weeks of pregnancy. Patients received two doses of 12 mg of betamethasone intramuscularly 24 hours apart. At the time of initial betamethasone administration, a Dexcom continuous glucose monitoring system was inserted which monitored tissue glucose levels every five minutes. Glucose levels were monitored for 7 days or until hospital discharge, whichever came first. We recorded the percentage of time women spent above three glucose thresholds: 110, 144, and 180 mg/dL. These thresholds were chosen as they have been associated with neonatal hypoglycemia in women in labor. Additionally, a comparison was made to a cohort of non-diabetic women of similar gestational ages who did not receive betamethasone. RESULTS: Seventeen women were enrolled at the time of betamethasone administration and data were available for 15 patients. There were 11 non-diabetic and 4 diabetic women. Five additional nondiabetic women who did not receive betamethasone served as controls. The average gestational age at enrollment was 29 2/7wk (range 25 1/7-34wk). Both diabetic and non-diabetic women had the highest recorded blood glucose readings between 24- 48 hours after the first injection of betamethasone. In that period, non-diabetic women spent 73%, 40%, and 17% of the time with blood glucose levels above the 110, 144, and 180 mg/dL thresholds, respectively. During a 24 hour monitoring period, non-diabetic women not receiving betamethasone spent 27%, 9%, and 0.2% above the same thresholds. At each glucose threshold, the difference between non-diabetics who did and did not receive betamethasone was statistically significant (P⫽0.003, P⫽0.03, P⫽0.01 respectively). CONCLUSION: Diabetic women receiving bethamethasone manifest significant hyperglycemia after betamethasone administration. This may need to be taken into account if delivery is imminent.
S98
OBJECTIVE: To evaluate the impact of maternal weight on the efficacy of 17-hydroxyprogesterone caproate (17P) for the prevention of preterm birth (PTB) in twin gestations and reduction of composite neonatal morbidity (CNM). We hypothesized that 17P would be more effective in non-obese women because a prior pharmacokinetic study had demonstrated a significant impact of maternal BMI upon 17P serum concentrations. STUDY DESIGN: A secondary analysis was performed on data from the Obstetrix trial of 17P in twins. 234 patients had recorded maternal weight and were included in the analysis. Pre-pregnancy maternal weight was calculated as quartiles (Q): Q1⫽97-133 pounds; Q2⫽133150 pounds; Q3⫽150-176 pounds; and Q4⫽176-332 pounds. PTB was defined as 2 categories: ⬍34 weeks and 34.0-36.9 weeks. Rates of PTB and CNM were calculated in each quartile for both the 17 P and placebo groups using the Fishers exact test. RESULTS: The rate of PTB .05). The rates of PTB .05). When BMI was used, the rate of PTB .05). When BMI was examined for PTB .05). Survival analysis showed that 17P did not significantly prolong pregnancy compared to placebo in any tercile of weight or BMI. CONCLUSION: 17P is not more effective in preventing PTB in lower weight categories, regardless of the definition used. This suggests that maternal weight does not explain the failure of 17P to prolong pregnancy in twins.
195 Differential expression of tunica internal endothelial cell kinase in the center and periphery of normal and growth restricted placentas Erica Heitmann1, Paul Singh1, Alok De1, Devika Maulik1, David Mundy1, Dev Maulik1 1 University of Missouri, Kansas City, Department of Obstetrics and Gynecology, Kansas City, MO
OBJECTIVE: Aberrant placental angiogenesis has a role in fetal growth restriction (FGR). Angiogenic factors have been found to differ between the center and periphery of normal placentas. Tunica Internal Endothelial Cell Kinase (Tie2) is an endothelial cell-specific receptor tyrosine kinase, whose activation is positively and negatively modulated by angiopoietin family. Angiopoietin-mediated modulation of Tie2 activation contributes to normal blood vessel development, maturation, maintenance, remodeling and stability. We have previously
American Journal of Obstetrics & Gynecology Supplement to JANUARY 2012