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88116 Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women
- Kara Marlatt, Dragana Lovre, Robbie Beyl, Chandra Tate, Evelyn Hayes, Charles Burant, Eric Ravussin, Franck Mauvais-Jarvis
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- Journal:
- Journal of Clinical and Translational Science / Volume 5 / Issue s1 / March 2021
- Published online by Cambridge University Press:
- 31 March 2021, p. 36
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ABSTRACT IMPACT: A short treatment of 8 obese postmenopausal women with conjugated estrogens and bazedoxifene does not alter insulin sensitivity or ectopic fat but increases serum markers of hepatic de novo lipogenesis and production of triacylglycerides. OBJECTIVES/GOALS: Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally-administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. METHODS/STUDY POPULATION: We conducted a randomized, double-blind, crossover pilot trial, testing the effect of CE/BZA on cardiometabolic health in postmenopausal women. Eight postmenopausal women (age 50-60 y, BMI 30-40 kg/m2) were randomization to an 8-week CE/BZA or placebo treatment separated by an 8-week washout period [NCT02274571]. The primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp), while secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); inflammatory markers; and serum metabolome (LC/MS). RESULTS/ANTICIPATED RESULTS: CE/BZA had no effect on insulin sensitivity, body composition, ectopic fat, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: p=0.06; high-dose clamp: p=0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs), and decreased long-chain acylcarnitines. These findings possibly reflect increased hepatic de novo FA synthesis and esterification into TAGs, and decreased FA oxidation, respectively (p<0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in lipoproteins (p<0.05). DISCUSSION/SIGNIFICANCE OF FINDINGS: A short treatment of postmenopausal women with CE/BZA did not alter insulin action or ectopic fat, but increased markers of hepatic de novo lipogenesis and TAG production. Study limitations include a small sample size and short treatment period. A larger, fully powered study is needed to validate the potential metabolic benefit of combining CE with BZA.
3266 Understanding epicardial adipose biology by imaging, transcriptomic, and lipidomic profiling
- Jadranka Stojanovska, Alex Tsodikov, Carey Lumeng, Charles Burant, Thomas Chenevert
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- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, pp. 157-158
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OBJECTIVES/SPECIFIC AIMS: The study aims to understand if pro inflammatory epicardial white adipose phenotype is positively associated with coronary atherosclerosis, while the brown adipose phenotype is negatively associated. Primary outcome is association between epicardial fat fraction and coronary atherosclerosis and cardiac function. Secondary outcome is transcriptomic and lipidomic profiling between epicardial, extra pericardial, and subcutaneous depots and how these profiles correlate with fat fraction. METHODS/STUDY POPULATION: Recruited patients undergoing open-heart surgery provided informed consent at their second visit and underwent laboratory testing and imaging (cardiac magnetic resonance including water-fat imaging and coronary calcium computed tomography) prior to their surgery. Cardiac function such as cardiac chamber volume, mass, function, and strain, and depo-specific fat fraction were calculated from cardiac MR and Agatston calcium score and epicardial adipose volume from CT images. At the time of surgery, a tissue specimens from the epicardial, extrapericardial, and subcutaneous depots were obtained for transcriptomic and lipidomic analysis. Linear and logistic regression analyses adjusted for other variables were performed to evaluate significance level between variables. RESULTS/ANTICIPATED RESULTS: 37 subjects were enrolled in the study, 13 (35%) of which were women. Cardiac function and fat fraction was quantified in all patients, whereas tissue analyses were performed in 22 patients. Epicardial and extrapericardial fat fraction were independently associated with coronary atherosclerosis (p-value 0.01 and 0.04 respectively) Only epicardial fat fraction was negatively associated with global circumferential shortening of the left ventricle (0.03), while neither the extrapericardial fat fraction nor epicardial adipose volume were not (p =0.33 and 0.97 respectively) All three adipose depots have unique gene signatures with differentially expressed genes and pathways. RNA sequencing of epicardial, extrapericardial, and subcutaneous depots demonstrated tight clustering of epicardial and subcutaneous signatures based on PCA analysis (Figure 2). 19 lipid classes and 59 lipids showed differential expression between at least 2 of the fat depots (Figure 3). Hierarchal clustering of the lipids showed that epicardial and extrapericardial depots were more closely related than subcutaneous adipose. Plasmenyl-phosphatidylcholines, with an ether-linked fatty acid at the sn-1 position of the lipid, were higher in subcutaneous fat while most other lipids were higher in epicardial fat per tissue weight, such as ceramides (p=0.002). DISCUSSION/SIGNIFICANCE OF IMPACT: Epicardial, extrapericardial, and subcutaneous adipose depots express different lipidome and transcriptome signatures and different pathways. GSEA analysis demonstrated enrichment of genes related to antigen presentation and B cell immunity in epicardial compared to subcutaneous adipose tissue. Epicardial fat fraction is associated with coronary atherosclerosis and decreased left ventricular global circumferential shortening as an early predictor of decreased left ventricular stroke volume. Epicardial fat fraction is also associated with cermides which may play role in the development of coronary atherosclerosis and decreased cardiac function.
First trimester maternal exposures to endocrine disrupting chemicals and metals and fetal size in the Michigan Mother–Infant Pairs study
- Jaclyn M. Goodrich, Mary E. Ingle, Steven E. Domino, Marjorie C. Treadwell, Dana C. Dolinoy, Charles Burant, John D. Meeker, Vasantha Padmanabhan
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- Journal:
- Journal of Developmental Origins of Health and Disease / Volume 10 / Issue 4 / August 2019
- Published online by Cambridge University Press:
- 30 January 2019, pp. 447-458
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Exposures to endocrine disrupting chemicals and metals are near ubiquitous worldwide, and their potential impact on children is a major public health concern. This pilot study was designed to characterize exposures to phthalates, phenols and metals among pregnant women in the first trimester, and to examine associations with fetal biometrics and birth weight. A total of 41 chemicals and elements were analyzed in urine from 56 mothers with full-term newborns from the Michigan Mother–Infant Pairs study. Bivariate analyses identified predictors of exposure biomarkers. Associations between birth weight, Fenton z-scores and second trimester fetal biometrics with toxicants were examined via multivariable linear regression. An average of 30 toxicants were detected in maternal urine. Fast food consumption was associated with several phthalate metabolites, phenols and metals, and canned food consumption with bisphenol F (P <0.05). Mono (3-carboxypropyl) phthalate was significantly associated with higher birth weight and Fenton z-score while the opposite was observed for bisphenol S. Estimated femur length from ultrasonography was significantly inversely associated with arsenic, barium and lead. While limited by sample size, this study is one of the first to evaluate birth outcomes with respect to emerging endocrine disrupting chemicals and to examine associations between toxicants and fetal biometrics. Exposure assessment was provided by the National Institute of Environmental Health Sciences’ Children’s Health Exposure Analysis Resource (NIEHS CHEAR), a resource available to children’s studies with the goal of combining data across cohorts in an effort to characterize the impact of toxicants on child health from birth and beyond.
2370: Understanding epicardial fat biology by imaging
- Jadranka Stojanovska, Thomas Chenevert, Alex Tsodikov, Carey Lumeng, Charles Burant
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- Journal:
- Journal of Clinical and Translational Science / Volume 1 / Issue S1 / September 2017
- Published online by Cambridge University Press:
- 10 May 2018, p. 63
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OBJECTIVES/SPECIFIC AIMS: The goal is to understand the underlying mechanism of epicaridial fat biology and its response to cardiometabolic disease by using quantitative multi-echo Dixon (mDixon) of water and lipid sequence, T2* blood-oxygen-level-dependent (BOLD) sequence of iron content, and data analysis methods to determine the quantity of brown Versus white fat. To accomplish this goal, we propose to define the histological, genetic, and metabolite state of epicardial fat and to confirm the relationship between fat phenotype and magnetic resonance (MR) characteristics. We will then investigate whether MR is more effective in identifying patients with lower cardiovascular disease risk than computed tomography (CT). METHODS/STUDY POPULATION: We will recruit 100 patients undergoing open-heart surgery and will quantify mDixon (proton density fat fraction), BOLD (T2*), and T2/T1 maps of epicardial, extrapericardial, and subcutaneous fat before their surgery. We will then (a) validate MR findings by direct depot-specific tissue analysis for lipid content, histological, and genetic markers of inflammation and brown and white fat, (b) develop plasma and fat depot specific metabolite profiling of cardiovascular disease risk and correlate with imaging characteristics. We will categorize cardiovascular risk score (Cardiovascular Health Status) of our 100 patients on quartiles. We will then build models where the categorized cardiovascular risk score are regressed on MR measures (epicardial fat fraction, T2*, and T2/T1 maps) and CT measures (epicardial fat volume and coronary calcium score). RESULTS/ANTICIPATED RESULTS: We anticipate to learn about epicardial fat biology and the role of inflammation in cardiometabolic disease. We will validate proton density fat fraction, T2* and T2 map against histology of epicardial fat for lipid content, established markers of brown and white fat and inflammation, respectively, to help us translate imaging technique to clinical practice. In respect to our second aim we anticipate that MR identifies patients at lower cardiovascular risk quartile than CT. DISCUSSION/SIGNIFICANCE OF IMPACT: Interest in epicardial fat as a visceral fat of the heart and coronary arteries is rapidly growing as the scientific based evidence indicates that the anatomic specificity is an important contributor to the cardiovascular diseases. The transformation of epicardial fat from a cardioprotective phenotype to a pro-inflammatory, atherosclerosis-promoting state triggers inflammation that is coincident with the expansion of epicardial fat volume detected by anatomic imaging. This study will impact the management of patients at risk for cardiovascular disease because it will demonstrate that quantification of epicardial fat status by MR identifies fat tissue changes validated by histology at lower cardiovascular disease risk quartile than CT.