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A compendium of G-protein-coupled receptors and cyclic nucleotide regulation of adipose tissue metabolism and energy expenditure.
Ceddia RP, Collins S
(2020) Clin Sci (Lond) 134: 473-512
MeSH Terms: Adipocytes, Adipose Tissue, Animals, Diabetes Mellitus, Type 2, Energy Metabolism, Humans, Lipolysis, Nucleotides, Cyclic, Receptors, G-Protein-Coupled, Signal Transduction
Show Abstract · Added March 26, 2020
With the ever-increasing burden of obesity and Type 2 diabetes, it is generally acknowledged that there remains a need for developing new therapeutics. One potential mechanism to combat obesity is to raise energy expenditure via increasing the amount of uncoupled respiration from the mitochondria-rich brown and beige adipocytes. With the recent appreciation of thermogenic adipocytes in humans, much effort is being made to elucidate the signaling pathways that regulate the browning of adipose tissue. In this review, we focus on the ligand-receptor signaling pathways that influence the cyclic nucleotides, cAMP and cGMP, in adipocytes. We chose to focus on G-protein-coupled receptor (GPCR), guanylyl cyclase and phosphodiesterase regulation of adipocytes because they are the targets of a large proportion of all currently available therapeutics. Furthermore, there is a large overlap in their signaling pathways, as signaling events that raise cAMP or cGMP generally increase adipocyte lipolysis and cause changes that are commonly referred to as browning: increasing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression and respiration.
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
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10 MeSH Terms
IL-10-producing B cells are enriched in murine pericardial adipose tissues and ameliorate the outcome of acute myocardial infarction.
Wu L, Dalal R, Cao CD, Postoak JL, Yang G, Zhang Q, Wang Z, Lal H, Van Kaer L
(2019) Proc Natl Acad Sci U S A 116: 21673-21684
MeSH Terms: Adipose Tissue, Animals, B-Lymphocytes, Chemokine CXCL13, Female, Inflammation, Interleukin-10, Interleukin-33, Lymphocyte Count, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Infarction, Pericardium, Regeneration
Show Abstract · Added March 3, 2020
Acute myocardial infarction (MI) provokes an inflammatory response in the heart that removes damaged tissues to facilitate tissue repair/regeneration. However, overactive and prolonged inflammation compromises healing, which may be counteracted by antiinflammatory mechanisms. A key regulatory factor in an inflammatory response is the antiinflammatory cytokine IL-10, which can be produced by a number of immune cells, including subsets of B lymphocytes. Here, we investigated IL-10-producing B cells in pericardial adipose tissues (PATs) and their role in the healing process following acute MI in mice. We found that IL-10-producing B cells were enriched in PATs compared to other adipose depots throughout the body, with the majority of them bearing a surface phenotype consistent with CD5 B-1a cells (CD5 B cells). These cells were detected early in life, maintained a steady presence during adulthood, and resided in fat-associated lymphoid clusters. The cytokine IL-33 and the chemokine CXCL13 were preferentially expressed in PATs and contributed to the enrichment of IL-10-producing CD5 B cells. Following acute MI, the pool of CD5 B cells was expanded in PATs. These cells accumulated in the infarcted heart during the resolution of MI-induced inflammation. B cell-specific deletion of IL-10 worsened cardiac function, exacerbated myocardial injury, and delayed resolution of inflammation following acute MI. These results revealed enrichment of IL-10-producing B cells in PATs and a significant contribution of these cells to the antiinflammatory processes that terminate MI-induced inflammation. Together, these findings have identified IL-10-producing B cells as therapeutic targets to improve the outcome of MI.
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16 MeSH Terms
Unknown actor in adipose tissue metabolism hiding in plain sight.
Collins S
(2019) Proc Natl Acad Sci U S A 116: 17145-17146
MeSH Terms: Adipose Tissue, Thermogenesis
Added July 22, 2020
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Extrinsic and Intrinsic Immunometabolism Converge: Perspectives on Future Research and Therapeutic Development for Obesity.
Caslin HL, Hasty AH
(2019) Curr Obes Rep 8: 210-219
MeSH Terms: Adaptive Immunity, Adipose Tissue, Animals, Energy Metabolism, Epigenesis, Genetic, Humans, Immunity, Immunologic Memory, Iron, Macrophages, Metabolic Diseases, Metabolic Networks and Pathways, MicroRNAs, Obesity
Show Abstract · Added March 3, 2020
PURPOSE OF REVIEW - Research over the past decade has shown that immunologic and metabolic pathways are intricately linked. This burgeoning field of immunometabolism includes intrinsic and extrinsic pathways and is known to be associated with obesity-accelerated metabolic disease. Intrinsic immunometabolism includes the study of fuel utilization and bioenergetic pathways that influence immune cell function. Extrinsic immunometabolism includes the study of immune cells and products that influence systemic metabolism.
RECENT FINDINGS - Th2 immunity, macrophage iron handling, adaptive immune memory, and epigenetic regulation of immunity, which all require intrinsic metabolic changes, play a role in systemic metabolism and metabolic function, linking the two arms of immunometabolism. Together, this suggests that targeting intrinsic immunometabolism can directly affect immune function and ultimately systemic metabolism. We highlight important questions for future basic research that will help improve translational research and provide therapeutic targets to help establish new treatments for obesity and associated metabolic disorders.
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MR fingerprinting with simultaneous T, T, and fat signal fraction estimation with integrated B correction reduces bias in water T and T estimates.
Ostenson J, Damon BM, Welch EB
(2019) Magn Reson Imaging 60: 7-19
MeSH Terms: Abdomen, Adipose Tissue, Algorithms, Bias, Computer Simulation, Fourier Analysis, Head, Humans, Image Processing, Computer-Assisted, Knee, Magnetic Resonance Imaging, Models, Statistical, Muscle, Skeletal, Phantoms, Imaging, Reproducibility of Results, Signal Processing, Computer-Assisted, Water
Show Abstract · Added March 3, 2020
PURPOSE - MR fingerprinting (MRF) sequences permit efficient T and T estimation in cranial and extracranial regions, but these areas may include substantial fat signals that bias T and T estimates. MRI fat signal fraction estimation is also a topic of active research in itself, but may be complicated by B heterogeneity and blurring during spiral k-space acquisitions, which are commonly used for MRF. An MRF method is proposed that separates fat and water signals, estimates water T and T, and accounts for B effects with spiral blurring correction, in a single sequence.
THEORY AND METHODS - A k-space-based fat-water separation method is further extended to unbalanced steady-state free precession MRF with swept echo time. Repeated application of this k-space fat-water separation to demodulated forms of the measured data allows a B map and correction to be approximated. The method is compared with MRF without fat separation across a broad range of fat signal fractions (FSFs), water Ts and Ts, and under heterogeneous static fields in simulations, phantoms, and in vivo.
RESULTS - The proposed method's FSF estimates had a concordance correlation coefficient of 0.990 with conventional measurements, and reduced biases in the T and T estimates due to fat signal relative to other MRF sequences by several hundred ms. The B correction improved the FSF, T, and T estimation compared to those estimates without correction.
CONCLUSION - The proposed method improves MRF water T and T estimation in the presence of fat and provides accurate FSF estimation with inline B correction.
Copyright © 2019 Elsevier Inc. All rights reserved.
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Tissue-Specific Differential Expression of Novel Genes and Long Intergenic Noncoding RNAs in Humans With Extreme Response to Evoked Endotoxemia.
Ferguson JF, Xue C, Gao Y, Tian T, Shi J, Zhang X, Wang Y, Li YD, Wei Z, Li M, Zhang H, Reilly MP
(2018) Circ Genom Precis Med 11: e001907
MeSH Terms: Adipose Tissue, Animals, Endotoxemia, Female, Gene Expression Regulation, Genome-Wide Association Study, Humans, Immunity, Innate, Inflammation, Male, Mice, Monocytes, RNA, Long Noncoding, RNA, Messenger, Sequence Analysis, RNA
Show Abstract · Added April 2, 2019
BACKGROUND - Cytokine responses to activation of innate immunity differ between individuals, yet the genomic and tissue-specific transcriptomic determinants of inflammatory responsiveness are not well understood. We hypothesized that tissue-specific mRNA and long intergenic noncoding RNA (lincRNA) induction differs between individuals with divergent evoked inflammatory responses.
METHODS - In the GENE Study (Genetics of Evoked Response to Niacin and Endotoxemia), we performed an inpatient endotoxin challenge (1 ng/kg lipopolysaccharide [LPS]) in healthy humans. We selected individuals in the top (high responders) and bottom (low responders) extremes of inflammatory responses and applied RNA sequencing to CD14 monocytes (N=15) and adipose tissue (N=25) before and after LPS administration.
RESULTS - Although only a small number of genes were differentially expressed at baseline, there were clear differences in the magnitude of the transcriptional response post-LPS between high and low responders, with a far greater number of genes differentially expressed by endotoxemia in high responders. Furthermore, tissue responses differed during inflammation, and we found a number of tissue-specific differentially expressed lincRNAs post-LPS, which we validated. Relative to nondifferentially expressed lincRNAs, differentially expressed lincRNAs were equally likely to be nonconserved as conserved between human and mouse, indicating that conservation is not a predictor of lincRNAs associated with human inflammatory pathophysiology. Differentially expressed genes also were enriched for signals with inflammatory and cardiometabolic disease in published genome-wide association studies. CTB-41I6.2 ( AC002091.1), a nonconserved human-specific lincRNA, is one of the top lincRNAs regulated by endotoxemia in monocytes, but not in adipose tissue. Knockdown experiments in THP-1 monocytes suggest that this lincRNA enhances LPS-induced interleukin 6 ( IL6) expression in monocytes, and we now refer to this as monocyte LPS-induced lincRNA regulator of IL6 ( MOLRIL6).
CONCLUSIONS - We highlight mRNAs and lincRNAs that represent novel candidates for modulation of innate immune and metabolic responses in humans.
CLINICAL TRIAL REGISTRATION - URL: https://www.clinicaltrials.gov . Unique identifier: NCT00953667.
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15 MeSH Terms
Relationships Between Adipose Mitochondrial Function, Serum Adiponectin, and Insulin Resistance in Persons With HIV After 96 Weeks of Antiretroviral Therapy.
Hulgan T, Ramsey BS, Koethe JR, Samuels DC, Gerschenson M, Libutti DE, Sax PE, Daar ES, McComsey GA, Brown TT
(2019) J Acquir Immune Defic Syndr 80: 358-366
MeSH Terms: Adiponectin, Adipose Tissue, Adult, DNA, Female, HIV Infections, HIV-1, Homeostasis, Humans, Insulin Resistance, Male, Middle Aged, Mitochondria, Obesity, RNA, Viral, Retrospective Studies, Viral Load
Show Abstract · Added December 11, 2019
OBJECTIVE - Some antiretroviral therapy (ART) and HIV itself confer metabolic risk, perhaps through altered mitochondrial function and adipokines. In AIDS Clinical Trials Group study A5224s, adipose mitochondrial DNA (mtDNA) levels decreased on ART, and electron transport chain complex I (CI) and complex IV (CIV) activity decreased. Another study found decreased serum adiponectin on ART with mtDNA mutation m.10398A>G. We hypothesized that decreased adipose tissue mitochondrial function would be associated with lower adiponectin and insulin sensitivity on ART, and m.10398G would influence these changes.
DESIGN - Retrospective analysis of an ART-naive substudy population from A5224s.
METHODS - Analyses included adipose mtDNA levels, CI and CIV activity by immunoassay, visceral adipose tissue by computed tomography, and fasting serum glucose at week 0 and week 96 of ART. Fasting insulin and adiponectin were measured from cryopreserved serum using multiplex bead array. Homeostasis model assessment-2 (HOMA2)-IR and HOMA2-%B estimated insulin resistance and β-cell function, respectively. The m.10398A>G mtDNA variant was available from existing genetic data.
RESULTS - Thirty-seven participants had adipose biopsies at week 0 and week 96. Percent decreases in CIV activity and adiponectin were correlated (Spearman rho 0.41; P = 0.01); this association persisted after controlling for age, sex, body mass index, or visceral adipose tissue in single-covariate regression. HOMA2-IR correlated with decreased CIV (-0.44; P = 0.01) and CI (-0.34; P = 0.05) activity. Among 12 non-Hispanic white persons, m.10398G was associated with decreased adiponectin (P = 0.04).
CONCLUSIONS - Decreased adipose mitochondrial activity correlated with changes in adiponectin and glucose homeostasis on ART. Previous findings that a mtDNA mutation modulates adiponectin levels in persons with HIV were replicated.
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Obesity-induced reduction of adipose eosinophils is reversed with low-calorie dietary intervention.
Bolus WR, Kennedy AJ, Hasty AH
(2018) Physiol Rep 6: e13919
MeSH Terms: Adipose Tissue, Animals, Caloric Restriction, Cells, Cultured, Eosinophils, Male, Mice, Mice, Inbred C57BL, Obesity, Weight Loss
Show Abstract · Added March 26, 2019
While many studies have characterized the inflammatory disposition of adipose tissue (AT) during obesity, far fewer have dissected how such inflammation resolves during the process of physiological weight loss. In addition, new immune cells, such as the eosinophil, have been discovered as part of the AT immune cell repertoire. We have therefore characterized how AT eosinophils, associated eosinophilic inflammation, and remodeling processes, fluctuate during a dietary intervention in obese mice. Similar to previous reports, we found that obesity induced by high-fat diet feeding reduced the AT eosinophil content. However, upon switching obese mice to a low fat diet, AT eosinophils were restored to lean levels as mice reached the body weight of controls. The rise in AT eosinophils during dietary weight loss was accompanied by reduced macrophage content and inflammatory expression, upregulated tissue remodeling factors, and a more uniformly distributed AT vascular network. Additionally, we show that eosinophils of another metabolically relevant tissue, the liver, did not oscillate with either dietary weight gain or weight loss. This study shows that eosinophil content is differentially regulated among tissues during the onset and resolution of obesity. Furthermore, AT eosinophils correlated with AT remodeling processes during weight loss and thus may play a role in reestablishing AT homeostasis.
© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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10 MeSH Terms
Fat-Water Phantoms for Magnetic Resonance Imaging Validation: A Flexible and Scalable Protocol.
Bush EC, Gifford A, Coolbaugh CL, Towse TF, Damon BM, Welch EB
(2018) J Vis Exp :
MeSH Terms: Adipose Tissue, Humans, Magnetic Resonance Imaging, Phantoms, Imaging, Water
Show Abstract · Added March 3, 2020
As new techniques are developed to image adipose tissue, methods to validate such protocols are becoming increasingly important. Phantoms, experimental replicas of a tissue or organ of interest, provide a low cost, flexible solution. However, without access to expensive and specialized equipment, constructing stable phantoms with high fat fractions (e.g., >50% fat fraction levels such as those seen in brown adipose tissue) can be difficult due to the hydrophobic nature of lipids. This work presents a detailed, low cost protocol for creating 5x 100 mL phantoms with fat fractions of 0%, 25%, 50%, 75%, and 100% using basic lab supplies (hotplate, beakers, etc.) and easily accessible components (distilled water, agar, water-soluble surfactant, sodium benzoate, gadolinium-diethylenetriaminepentacetate (DTPA) contrast agent, peanut oil, and oil-soluble surfactant). The protocol was designed to be flexible; it can be used to create phantoms with different fat fractions and a wide range of volumes. Phantoms created with this technique were evaluated in the feasibility study that compared the fat fraction values from fat-water magnetic resonance imaging to the target values in the constructed phantoms. This study yielded a concordance correlation coefficient of 0.998 (95% confidence interval: 0.972-1.00). In summary, these studies demonstrate the utility of fat phantoms for validating adipose tissue imaging techniques across a range of clinically relevant tissues and organs.
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High CD8 T-Cell Receptor Clonality and Altered CDR3 Properties Are Associated With Elevated Isolevuglandins in Adipose Tissue During Diet-Induced Obesity.
McDonnell WJ, Koethe JR, Mallal SA, Pilkinton MA, Kirabo A, Ameka MK, Cottam MA, Hasty AH, Kennedy AJ
(2018) Diabetes 67: 2361-2376
MeSH Terms: Adipose Tissue, Animals, CD8-Positive T-Lymphocytes, Complementarity Determining Regions, Diet, High-Fat, Glucose Tolerance Test, Insulin Resistance, Liver, Male, Mice, Obesity, Prostaglandins
Show Abstract · Added March 26, 2019
Adipose tissue (AT) CD4 and CD8 T cells contribute to obesity-associated insulin resistance. Prior studies identified conserved T-cell receptor (TCR) chain families in obese AT, but the presence and clonal expansion of specific TCR sequences in obesity has not been assessed. We characterized AT and liver CD8 and CD4 TCR repertoires of mice fed a low-fat diet (LFD) and high-fat diet (HFD) using deep sequencing of the TCRβ chain to quantify clonal expansion, gene usage, and CDR3 sequence. In AT CD8 T cells, HFD reduced TCR diversity, increased the prevalence of public TCR clonotypes, and selected for TCR CDR3 regions enriched in positively charged and less polarized amino acids. Although TCR repertoire alone could distinguish between LFD- and HFD-fed mice, these properties of the CDR3 region of AT CD8 T cells from HFD-fed mice led us to examine the role of negatively charged and nonpolar isolevuglandin (isoLG) adduct-containing antigen-presenting cells within AT. IsoLG-adducted protein species were significantly higher in AT macrophages of HFD-fed mice; isoLGs were elevated in M2-polarized macrophages, promoting CD8 T-cell activation. Our findings demonstrate that clonal TCR expansion that favors positively charged CDR3s accompanies HFD-induced obesity, which may be an antigen-driven response to isoLG accumulation in macrophages.
© 2018 by the American Diabetes Association.
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