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Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family-Based Linkage and Association in the IRAS Family Study.
Tabb KL, Hellwege JN, Palmer ND, Dimitrov L, Sajuthi S, Taylor KD, Ng MC, Hawkins GA, Chen YI, Brown WM, McWilliams D, Williams A, Lorenzo C, Norris JM, Long J, Rotter JI, Curran JE, Blangero J, Wagenknecht LE, Langefeld CD, Bowden DW
(2017) Ann Hum Genet 81: 49-58
MeSH Terms: Adiponectin, Adolescent, Adult, Aged, Aged, 80 and over, Atherosclerosis, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Resistance, Lipids, Lod Score, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Young Adult
Show Abstract · Added April 10, 2018
Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (P < 5 × 10 ), with the strongest association between rs651821:C>T in APOA5 and triglyceride levels (P  =  3.67 × 10 ). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to the Database of Single Nucleotide Polymorphisms (dbSNP) build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.
© 2017 John Wiley & Sons Ltd/University College London.
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MeSH Terms
Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice.
Satoh M, Hoshino M, Fujita K, Iizuka M, Fujii S, Clingan CS, Van Kaer L, Iwabuchi K
(2016) Sci Rep 6: 28473
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adiponectin, Animals, Antigen Presentation, Antigens, CD1d, B7-1 Antigen, Diet, High-Fat, Disease Models, Animal, Disease Progression, Galactosylceramides, Insulin Resistance, Interferon-gamma, Lymphocyte Activation, Macrophage Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Natural Killer T-Cells, Obesity
Show Abstract · Added July 30, 2016
It has been shown that CD1d expression and glycolipid-reactive, CD1d-restricted NKT cells exacerbate the development of obesity and insulin resistance in mice. However, the relevant CD1d-expressing cells that influence the effects of NKT cells on the progression of obesity remain incompletely defined. In this study, we have demonstrated that 3T3-L1 adipocytes can present endogenous ligands to NKT cells, leading to IFN-γ production, which in turn, stimulated 3T3-L1 adipocytes to enhance expression of CD1d and CCL2, and decrease expression of adiponectin. Furthermore, adipocyte-specific CD1d deletion decreased the size of the visceral adipose tissue mass and enhanced insulin sensitivity in mice fed a high-fat diet (HFD). Accordingly, NKT cells were less activated, IFN-γ production was significantly reduced, and levels of adiponectin were increased in these animals as compared with control mice on HFD. Importantly, macrophage recruitment into the adipose tissue of adipocyte-specific CD1d-deficient mice was significantly blunted. These findings indicate that interactions between NKT cells and CD1d-expressing adipocytes producing endogenous NKT cell ligands play a critical role in the induction of inflammation and functional modulation of adipose tissue that leads to obesity.
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21 MeSH Terms
Sustained Brown Fat Stimulation and Insulin Sensitization by a Humanized Bispecific Antibody Agonist for Fibroblast Growth Factor Receptor 1/βKlotho Complex.
Kolumam G, Chen MZ, Tong R, Zavala-Solorio J, Kates L, van Bruggen N, Ross J, Wyatt SK, Gandham VD, Carano RA, Dunshee DR, Wu AL, Haley B, Anderson K, Warming S, Rairdan XY, Lewin-Koh N, Zhang Y, Gutierrez J, Baruch A, Gelzleichter TR, Stevens D, Rajan S, Bainbridge TW, Vernes JM, Meng YG, Ziai J, Soriano RH, Brauer MJ, Chen Y, Stawicki S, Kim HS, Comps-Agrar L, Luis E, Spiess C, Wu Y, Ernst JA, McGuinness OP, Peterson AS, Sonoda J
(2015) EBioMedicine 2: 730-43
MeSH Terms: Adiponectin, Adipose Tissue, Brown, Animals, Antibodies, Bispecific, Cell Line, Energy Metabolism, Fibroblast Growth Factors, HEK293 Cells, Humans, Insulin, Macaca fascicularis, Male, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Obese, Protein Binding, Receptor, Fibroblast Growth Factor, Type 1, Thermogenesis, Weight Loss
Show Abstract · Added September 10, 2015
Dissipating excess calories as heat through therapeutic stimulation of brown adipose tissues (BAT) has been proposed as a potential treatment for obesity-linked disorders. Here, we describe the generation of a humanized effector-less bispecific antibody that activates fibroblast growth factor receptor (FGFR) 1/βKlotho complex, a common receptor for FGF21 and FGF19. Using this molecule, we show that antibody-mediated activation of FGFR1/βKlotho complex in mice induces sustained energy expenditure in BAT, browning of white adipose tissue, weight loss, and improvements in obesity-associated metabolic derangements including insulin resistance, hyperglycemia, dyslipidemia and hepatosteatosis. In mice and cynomolgus monkeys, FGFR1/βKlotho activation increased serum high-molecular-weight adiponectin, which appears to contribute over time by enhancing the amplitude of the metabolic benefits. At the same time, insulin sensitization by FGFR1/βKlotho activation occurs even before the onset of weight loss in a manner that is independent of adiponectin. Together, selective activation of FGFR1/βKlotho complex with a long acting therapeutic antibody represents an attractive approach for the treatment of type 2 diabetes and other obesity-linked disorders through enhanced energy expenditure, insulin sensitization and induction of high-molecular-weight adiponectin.
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20 MeSH Terms
Insulin-independent role of adiponectin receptor signaling in Drosophila germline stem cell maintenance.
Laws KM, Sampson LL, Drummond-Barbosa D
(2015) Dev Biol 399: 226-36
MeSH Terms: Adipocytes, Animals, Animals, Genetically Modified, Cloning, Molecular, DNA Primers, Drosophila, Drosophila Proteins, Female, Gene Expression Regulation, Developmental, Germ Cells, Image Processing, Computer-Assisted, Insulin, Microscopy, Fluorescence, Ovary, Receptors, Adiponectin, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Stem Cells
Show Abstract · Added March 19, 2017
Adipocytes have key endocrine roles, mediated in large part by secreted protein hormones termed adipokines. The adipokine adiponectin is well known for its role in sensitizing peripheral tissues to insulin, and several lines of evidence suggest that adiponectin might also modulate stem cells/precursors. It remains unclear, however, how adiponectin signaling controls stem cells and whether this role is secondary to its insulin-sensitizing effects or distinct. Drosophila adipocytes also function as an endocrine organ and, although no obvious adiponectin homolog has been identified, Drosophila AdipoR encodes a well-conserved homolog of mammalian adiponectin receptors. Here, we generate a null AdipoR allele and use clonal analysis to demonstrate an intrinsic requirement for AdipoR in germline stem cell (GSC) maintenance in the Drosophila ovary. AdipoR null GSCs are not fully responsive to bone morphogenetic protein ligands from the niche and have a slight reduction in E-cadherin levels at the GSC-niche junction. Conversely, germline-specific overexpression of AdipoR inhibits natural GSC loss, suggesting that reduction in adiponectin signaling might contribute to the normal decline in GSC numbers observed over time in wild-type females. Surprisingly, AdipoR is not required for insulin sensitization of the germline, leading us to speculate that insulin sensitization is a more recently acquired function than stem cell regulation in the evolutionary history of adiponectin signaling. Our findings establish Drosophila female GSCs as a new system for future studies addressing the molecular mechanisms whereby adiponectin receptor signaling modulates stem cell fate.
Copyright © 2015 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Empirical characteristics of family-based linkage to a complex trait: the ADIPOQ region and adiponectin levels.
Hellwege JN, Palmer ND, Mark Brown W, Brown MW, Ziegler JT, Sandy An S, An SS, Guo X, Ida Chen YD, Chen IY, Taylor K, Hawkins GA, Ng MC, Speliotes EK, Lorenzo C, Norris JM, Rotter JI, Wagenknecht LE, Langefeld CD, Bowden DW
(2015) Hum Genet 134: 203-13
MeSH Terms: Adiponectin, Adolescent, Adult, Aged, Aged, 80 and over, Databases, Nucleic Acid, Datasets as Topic, Family, Female, Genetic Linkage, Genetic Loci, Hispanic Americans, Humans, Lod Score, Male, Microsatellite Repeats, Middle Aged, Polymorphism, Single Nucleotide
Show Abstract · Added September 15, 2015
We previously identified a low-frequency (1.1 %) coding variant (G45R; rs200573126) in the adiponectin gene (ADIPOQ) which was the basis for a multipoint microsatellite linkage signal (LOD = 8.2) for plasma adiponectin levels in Hispanic families. We have empirically evaluated the ability of data from targeted common variants, exome chip genotyping, and genome-wide association study data to detect linkage and association to adiponectin protein levels at this locus. Simple two-point linkage and association analyses were performed in 88 Hispanic families (1,150 individuals) using 10,958 SNPs on chromosome 3. Approaches were compared for their ability to map the functional variant, G45R, which was strongly linked (two-point LOD = 20.98) and powerfully associated (p value = 8.1 × 10(-50)). Over 450 SNPs within a broad 61 Mb interval around rs200573126 showed nominal evidence of linkage (LOD > 3) but only four other SNPs in this region were associated with p values < 1.0 × 10(-4). When G45R was accounted for, the maximum LOD score across the interval dropped to 4.39 and the best p value was 1.1 × 10(-5). Linked and/or associated variants ranged in frequency (0.0018-0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r (2) < 0.20). In addition, the two-point linkage approach empirically outperformed multipoint microsatellite and multipoint SNP analysis. In the absence of data for rs200573126, family-based linkage analysis using a moderately dense SNP dataset, including both common and low-frequency variants, resulted in stronger evidence for an adiponectin locus than association data alone. Thus, linkage analysis can be a useful tool to facilitate identification of high-impact genetic variants.
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18 MeSH Terms
Administration of IL-1ra improves adiponectin levels in chronic hemodialysis patients.
Hung AM, Limkunakul C, Placido JS, Siew ED, Ellis CD, Shintani A, Ikizler TA
(2014) J Nephrol 27: 681-8
MeSH Terms: Adiponectin, Adult, Aged, Anti-Inflammatory Agents, Biomarkers, Female, Humans, Inflammation, Insulin Resistance, Interleukin 1 Receptor Antagonist Protein, Leptin, Male, Middle Aged, Pilot Projects, Renal Dialysis, Renal Insufficiency, Chronic, Tennessee, Time Factors, Treatment Outcome, Up-Regulation
Show Abstract · Added March 21, 2014
BACKGROUND - Adiponectin, an adipose tissue derived hormone, is known to have insulin-sensitizing, anti-inflammatory, and anti-atherogenic properties in the general population. Adiponectin secretion is suppressed by systemic inflammation, a highly prevalent condition in maintenance hemodialysis (MHD) patients. We evaluated whether short-term administration of interleukin 1 receptor antagonist (IL-1ra) improves adiponectin levels and insulin sensitivity in MHD patients.
METHODS - Ad hoc analysis was performed on a pilot randomized placebo-controlled trial of the administration of IL-1ra in chronically inflamed MHD patients. Twenty-two patients were randomly assigned to receive 100 mg of IL-1ra or placebo (1:1) for 4 weeks, and 14 completed the trial. ANCOVA was used to compare percent change from baseline to 4 weeks. The primary outcome was percent change in adiponectin and the secondary outcomes were changes in leptin, homeostatic model assessment of insulin resistance (HOMA-IR) and the leptin-to-adiponectin ratio (LAR).
RESULTS - Patients' mean age was 49 ± 13 years, and 71 % were males. At baseline, the median values for adiponectin, leptin, LAR and HOMA-IR were 11.5 μg/ml [interquartile range (IQR) 9, 28.5], 17.8 ng/ml (3.9, 50.0), 2.20 (0.13, 3.98), and 2.8 (2.0, 3.6), respectively. IL-1ra administration resulted in a mean percent increase in serum adiponectin of 22 % vs. 14 % decrease in the placebo arm (p = 0.003). Leptin, LAR or HOMA-IR levels did not change in either arm.
CONCLUSIONS - Short-term administration of IL-1ra significantly increased adiponectin levels among prevalent MHD patients. The intervention did not impact insulin sensitivity parameters. Studies of longer duration and larger sample size are needed to further evaluate the potential effect of anti-inflammatory interventions on metabolic markers and insulin sensitivity in MHD patients.
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20 MeSH Terms
One generation's "junk" is another's treasure: the emerging role of microRNAs as therapeutic targets.
Brittain EL, Hemnes AR
(2014) J Heart Lung Transplant 33: 233-4
MeSH Terms: Heart Failure, Humans, MicroRNAs, Myocytes, Cardiac, Receptors, Adiponectin
Added February 28, 2014
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5 MeSH Terms
Glycemic load is associated with oxidative stress among prevalent maintenance hemodialysis patients.
Limkunakul C, Sundell MB, Pouliot B, Graves AJ, Shintani A, Ikizler TA
(2014) Nephrol Dial Transplant 29: 1047-53
MeSH Terms: Absorptiometry, Photon, Adiponectin, Adult, Biomarkers, Blood Glucose, Cross-Sectional Studies, Diet, Female, Glycemic Index, Humans, Inflammation, Leptin, Male, Middle Aged, Oxidative Stress, Renal Dialysis, Retrospective Studies
Show Abstract · Added September 29, 2014
BACKGROUND - High glycemic index (GI) and glycemic load (GL) are associated with increased levels of oxidative stress and systemic inflammation in the general population. Maintenance hemodialysis (MHD) patients are known to have excessive oxidative stress burden and inflammation. In this study, we examined the relationship between dietary GI or GL and markers of oxidative stress or inflammation among prevalent MHD patients.
METHODS - A registered dietitian obtained GI, GL and other dietary data from 58 MHD patients. Two separate 24-h diet recalls (a hemodialysis day and a non-hemodialysis day) were analyzed using the Nutrition Data System for Research (NDS-R) software. Plasma or serum concentrations of F2-isoprostanes, high sensitivity C-reactive protein (hsCRP), leptin and adiponectin (ADPN) were measured in fasting state. Fat mass was measured by dual-energy X-ray absorptiometry (DEXA). Cross-sectional associations between GI, GL and markers of interest were examined by multiple regression analysis with adjustment for potential covariates.
RESULTS - Mean (±SD) age, body mass index (BMI) and total trunk fat were 47 ± 12 years, 29.5 ± 6.8 kg/m(2) and 16.4 ± 8.8 kg, respectively. Dietary GI was associated with trunk fat (r = -0.182, P = 0.05) but not with F2-isoprostanes and hsCRP. In contrast, GL was significantly associated with F2-isoprostanes (P = 0.002), in unadjusted analysis, which remained in adjusted analyses, adjusting for age and sex (P = 0.005), and after adjusting for BMI, trunk fat and waist/hip ratio (P = 0.004). Addition of leptin or ADPN did not alter the significance of the association. GL also correlated with hsCRP (P = 0.03), but this association was modified by BMI and trunk fat.
CONCLUSIONS - Dietary GL is significantly associated with markers of oxidative stress and inflammation among prevalent MHD patients, independent of the body composition and adipocytokines. These data indicate the importance of the contents of dietary nutrient intake composition and its potential role in determining the metabolic disturbances in MHD patients.
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17 MeSH Terms
A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2.
Wu Y, Gao H, Li H, Tabara Y, Nakatochi M, Chiu YF, Park EJ, Wen W, Adair LS, Borja JB, Cai Q, Chang YC, Chen P, Croteau-Chonka DC, Fogarty MP, Gan W, He CT, Hsiung CA, Hwu CM, Ichihara S, Igase M, Jo J, Kato N, Kawamoto R, Kuzawa CW, Lee JJ, Liu J, Lu L, McDade TW, Osawa H, Sheu WH, Teo Y, Vadlamudi S, Van Dam RM, Wang Y, Xiang YB, Yamamoto K, Ye X, Young TL, Zheng W, Zhu J, Shu XO, Shin C, Jee SH, Chuang LM, Miki T, Yokota M, Lin X, Mohlke KL, Tai ES
(2014) Hum Mol Genet 23: 1108-19
MeSH Terms: Adiponectin, Asian Continental Ancestry Group, Cardiovascular Diseases, Cohort Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Membrane Proteins, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins, Receptor, Fibroblast Growth Factor, Type 2
Show Abstract · Added March 7, 2014
Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10(-4)), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10(-4)) and body mass index (BMI)-adjusted waist-hip ratio (P = 9.8 × 10(-3)). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.
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12 MeSH Terms
Impact of hematopoietic cyclooxygenase-1 deficiency on obesity-linked adipose tissue inflammation and metabolic disorders in mice.
Saraswathi V, Ramnanan CJ, Wilks AW, Desouza CV, Eller AA, Murali G, Ramalingam R, Milne GL, Coate KC, Edgerton DS
(2013) Metabolism 62: 1673-85
MeSH Terms: Adiponectin, Adipose Tissue, Animals, Biomarkers, Blotting, Western, Bone Marrow Cells, Bone Marrow Transplantation, Cyclooxygenase 1, Diet, High-Fat, Eating, Female, Fluorescent Antibody Technique, Inflammation, Kidney, Leptin, Liver, Macrophages, Mice, Mice, Knockout, Obesity, Real-Time Polymerase Chain Reaction, Weight Gain
Show Abstract · Added March 26, 2014
OBJECTIVE - Adipose tissue (AT)-specific inflammation is considered to mediate the pathological consequences of obesity and macrophages are known to activate inflammatory pathways in obese AT. Because cyclooxygenases play a central role in regulating the inflammatory processes, we sought to determine the role of hematopoietic cyclooxygenase-1 (COX-1) in modulating AT inflammation in obesity.
MATERIALS/METHODS - Bone marrow transplantation was performed to delete COX-1 in hematopoietic cells. Briefly, female wild type (wt) mice were lethally irradiated and injected with bone marrow (BM) cells collected from wild type (COX-1+/+) or COX-1 knock-out (COX-1-/-) donor mice. The mice were fed a high fat diet for 16 weeks.
RESULTS - The mice that received COX-1-/- bone marrow (BM-COX-1-/-) exhibited a significant increase in fasting glucose, total cholesterol and triglycerides in the circulation compared to control (BM-COX-1+/+) mice. Markers of AT-inflammation were increased and were associated with increased leptin and decreased adiponectin in plasma. Hepatic inflammation was reduced with a concomitant reduction in TXB2 levels. The hepatic mRNA expression of genes involved in lipogenesis and lipid transport was increased while expression of genes involved in regulating hepatic glucose output was reduced in BM-COX-1-/- mice. Finally, renal inflammation and markers of renal glucose release were increased in BM-COX-1-/- mice.
CONCLUSION - Hematopoietic COX-1 deletion results in impairments in metabolic homeostasis which may be partly due to increased AT inflammation and dysregulated adipokine profile. An increase in renal glucose release and hepatic lipogenesis/lipid transport may also play a role, at least in part, in mediating hyperglycemia and dyslipidemia, respectively.
Published by Elsevier Inc.
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22 MeSH Terms