Mechanisms linking adipose tissue inflammation to cardiac hypertrophy and fibrosis

Abstract Adipose tissue is classically recognized as the primary site of lipid storage, but in recent years has garnered appreciation for its broad role as an endocrine organ comprising multiple cell types whose collective secretome, termed as adipokines, is highly interdependent on metabolic homeostasis and inflammatory state. Anatomical location (e.g. visceral, subcutaneous, epicardial etc) and cellular composition of adipose tissue (e.g. white, beige, and brown adipocytes, macrophages etc.) also plays a critical role in determining its response to metabolic state, the resulting secretome, and its potential impact on remote tissues. Compared with other tissues, the heart has an extremely high and constant demand for energy generation, of which most is derived from oxidation of fatty acids. Availability of this fatty acid fuel source is dependent on adipose tissue, but evidence is mounting that adipose tissue plays a much broader role in cardiovascular physiology. In this review, we discuss the impact of the brown, subcutaneous, and visceral white, perivascular (PVAT), and epicardial adipose tissue (EAT) secretome on the development and progression of cardiovascular disease (CVD), with a particular focus on cardiac hypertrophy and fibrosis.

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Genome-wide CRISPR screen for PARKIN regulators reveals transcriptional repression as a determinant of mitophagy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1711023115 ◽

2017 ◽

Vol 115 (2) ◽

pp. E180-E189 ◽

Cited By ~ 33

Author(s):

Christoph Potting ◽

Christophe Crochemore ◽

Francesca Moretti ◽

Florian Nigsch ◽

Isabel Schmidt ◽

...

Keyword(s):

Transcriptional Repression ◽

Critical Role ◽

Induced Pluripotent Stem Cell ◽

Cell Types ◽

Physiological Regulation ◽

Genome Wide ◽

Crispr Screen ◽

Multiple Cell ◽

Induced Pluripotent ◽

The Impact

PARKIN, an E3 ligase mutated in familial Parkinson’s disease, promotes mitophagy by ubiquitinating mitochondrial proteins for efficient engagement of the autophagy machinery. Specifically, PARKIN-synthesized ubiquitin chains represent targets for the PINK1 kinase generating phosphoS65-ubiquitin (pUb), which constitutes the mitophagy signal. Physiological regulation of PARKIN abundance, however, and the impact on pUb accumulation are poorly understood. Using cells designed to discover physiological regulators of PARKIN abundance, we performed a pooled genome-wide CRISPR/Cas9 knockout screen. Testing identified genes individually resulted in a list of 53 positive and negative regulators. A transcriptional repressor network including THAP11 was identified and negatively regulates endogenous PARKIN abundance. RNAseq analysis revealed the PARKIN-encoding locus as a prime THAP11 target, and THAP11 CRISPR knockout in multiple cell types enhanced pUb accumulation. Thus, our work demonstrates the critical role of PARKIN abundance, identifies regulating genes, and reveals a link between transcriptional repression and mitophagy, which is also apparent in human induced pluripotent stem cell-derived neurons, a disease-relevant cell type.

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MUNIn (Multiple cell-type UNifying long-range chromatin Interaction detector): a statistical framework for identifying long-range chromatin interactions from multiple cell types

10.1101/2020.11.12.380782 ◽

2020 ◽

Author(s):

Weifang Liu ◽

Armen Abnousi ◽

Qian Zhang ◽

Yun Li ◽

Ming Hu ◽

...

Keyword(s):

Long Range ◽

Spatial Organization ◽

Critical Role ◽

Cell Types ◽

Chromatin Interaction ◽

Cell Type ◽

Statistical Framework ◽

Chromatin Interactions ◽

The Status ◽

Multiple Cell

AbstractChromatin spatial organization (interactome) plays a critical role in genome function. Deep understanding of chromatin interactome can shed insights into transcriptional regulation mechanisms and human disease pathology. One essential task in the analysis of chromatin interactomic data is to identify long-range chromatin interactions. Existing approaches, such as HiCCUPS, FitHiC/FitHiC2 and FastHiC, are all designed for analyzing individual cell types. None of them accounts for unbalanced sequencing depths and heterogeneity among multiple cell types in a unified statistical framework. To fill in the gap, we have developed a novel statistical framework MUNIn (Multiple cell-type UNifying long-range chromatin Interaction detector) for identifying long-range chromatin interactions from multiple cell types. MUNIn adopts a hierarchical hidden Markov random field (H-HMRF) model, in which the status (peak or background) of each interacting chromatin loci pair depends not only on the status of loci pairs in its neighborhood region, but also on the status of the same loci pair in other cell types. To benchmark the performance of MUNIn, we performed comprehensive simulation studies and real data analysis, and showed that MUNIn can achieve much lower false positive rates for detecting cell-type-specific interactions (33.1 - 36.2%), and much enhanced statistical power for detecting shared peaks (up to 74.3%), compared to uni-cell-type analysis. Our data demonstrated that MUNIn is a useful tool for the integrative analysis of interactomic data from multiple cell types.

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Advanced glycation end-products regulate extracellular matrix-adipocyte metabolic crosstalk in diabetes

Scientific Reports ◽

10.1038/s41598-019-56242-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Clarissa Strieder-Barboza ◽

Nicki A. Baker ◽

Carmen G. Flesher ◽

Monita Karmakar ◽

Christopher K. Neeley ◽

...

Keyword(s):

Extracellular Matrix ◽

Adipose Tissue ◽

Glucose Uptake ◽

Rho Gtpases ◽

Cell Types ◽

Scavenger Receptors ◽

Advanced Glycation ◽

Human Diabetes ◽

Multiple Cell ◽

Underlying Mechanisms

AbstractThe adipose tissue extracellular matrix (ECM) regulates adipocyte cellular metabolism and is altered in obesity and type 2 diabetes, but mechanisms underlying ECM-adipocyte metabolic crosstalk are poorly defined. Advanced glycation end-product (AGE) formation is increased in diabetes. AGE alter tissue function via direct effects on ECM and by binding scavenger receptors on multiple cell types and signaling through Rho GTPases. Our goal was to determine the role and underlying mechanisms of AGE in regulating human ECM-adipocyte metabolic crosstalk. Visceral adipocytes from diabetic and non-diabetic humans with obesity were studied in 2D and 3D-ECM culture systems. AGE is increased in adipose tissue from diabetic compared to non-diabetic subjects. Glycated collagen 1 and AGE-modified ECM regulate adipocyte glucose uptake and expression of AGE scavenger receptors and Rho signaling mediators, including the DIAPH1 gene, which encodes the human Diaphanous 1 protein (hDia1). Notably, inhibition of hDia1, but not scavenger receptors RAGE or CD36, attenuated AGE-ECM inhibition of adipocyte glucose uptake. These data demonstrate that AGE-modification of ECM contributes to adipocyte insulin resistance in human diabetes, and implicate hDia1 as a potential mediator of AGE-ECM-adipocyte metabolic crosstalk.

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A New Organotypic Culture of Adipose Tissue Fragments Maintains Viable Mature Adipocytes for a Long Term, Together with Development of Immature Adipocytes and Mesenchymal Stem Cell-Like Cells

Endocrinology ◽

10.1210/en.2008-0525 ◽

2008 ◽

Vol 149 (10) ◽

pp. 4794-4798 ◽

Cited By ~ 32

Author(s):

Emiko Sonoda ◽

Shigehisa Aoki ◽

Kazuyoshi Uchihashi ◽

Hidenobu Soejima ◽

Sachiko Kanaji ◽

...

Keyword(s):

Adipose Tissue ◽

Organotypic Culture ◽

Three Dimensional ◽

Collagen Gel ◽

Cell Types ◽

Ppar Γ ◽

Tnf Α ◽

Multiple Cell ◽

Related Agent

Adipose tissue that consists of mature and immature adipocytes is suggested to contain mesenchymal stem cells (MSCs), but a culture system for analyzing their cell types within the tissue has not been established. Here we show that three-dimensional collagen gel culture of rat sc adipose tissue fragments maintained viable mature adipocytes for a long term, producing immature adipocytes and MSC-like cells from the fragments, using immunohistochemistry, ELISA, and real time RT-PCR. Bromodeoxyuridine uptake of mature adipocytes was detected. Adiponectin and leptin, and adipocyte-specific genes of adiponectin, leptin, and PPAR-γ were detected in culture assembly, whereas the lipogenesis factor insulin (20 mU/ml) and inflammation-related agent TNF-α (2 nm) increased and decreased, respectively, all of their displays. Both spindle-shaped cell types with oil red O-positive lipid droplets and those with expression of MSC markers (CD105 and CD44) developed around the fragments. The data indicate that adipose tissue-organotypic culture retains unilocular structure, proliferative ability, and some functions of mature adipocytes, generating both immature adipocytes and CD105+/CD44+ MSC-like cells. This suggests that our method will open up a new way for studying both multiple cell types within adipose tissue and the cell-based mechanisms of obesity and metabolic syndrome.

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Adipose Tissue: A Source of Stem Cells with Potential for Regenerative Therapies for Wound Healing

Journal of Clinical Medicine ◽

10.3390/jcm9072161 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2161 ◽

Cited By ~ 1

Author(s):

Lucy V Trevor ◽

Kirsten Riches-Suman ◽

Ajay L Mahajan ◽

M Julie Thornton

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Adipose Tissue ◽

Cell Types ◽

Anatomical Location ◽

Impaired Wound Healing ◽

Cell Lineages ◽

Different Types ◽

No Gold Standard ◽

Regenerative Therapies

Interest in adipose tissue is fast becoming a focus of research after many years of being considered as a simple connective tissue. It is becoming increasingly apparent that adipose tissue contains a number of diverse cell types, including adipose-derived stem cells (ASCs) with the potential to differentiate into a number of cell lineages, and thus has significant potential for developing therapies for regenerative medicine. Currently, there is no gold standard treatment for scars and impaired wound healing continues to be a challenge faced by clinicians worldwide. This review describes the current understanding of the origin, different types, anatomical location, and genetics of adipose tissue before discussing the properties of ASCs and their promising applications for tissue engineering, scarring, and wound healing.

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Platelet abnormalities in Huntington’s disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-318854 ◽

2018 ◽

Vol 90 (3) ◽

pp. 272-283 ◽

Cited By ~ 7

Author(s):

Hélèna L Denis ◽

Jérôme Lamontagne-Proulx ◽

Isabelle St-Amour ◽

Sarah L Mason ◽

Jesse W Rowley ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Cell Types ◽

Vascular Abnormalities ◽

Matched Healthy Control ◽

Healthy Control ◽

Multiple Cell ◽

The Impact ◽

Psychiatric Problems ◽

Platelet Depletion

Huntington’s disease (HD) is a hereditary disorder that typically manifests in adulthood with a combination of motor, cognitive and psychiatric problems. The pathology is caused by a mutation in the huntingtin gene which results in the production of an abnormal protein, mutant huntingtin (mHtt). This protein is ubiquitously expressed and known to confer toxicity to multiple cell types. We have recently reported that HD brains are also characterised by vascular abnormalities, which include changes in blood vessel density/diameter as well as increased blood–brain barrier (BBB) leakage.ObjectivesSeeking to elucidate the origin of these vascular and BBB abnormalities, we studied platelets that are known to play a role in maintaining the integrity of the vasculature and thrombotic pathways linked to this, given they surprisingly contain the highest concentration of mHtt of all blood cells.MethodsWe assessed the functional status of platelets by performing ELISA, western blot and RNA sequencing in a cohort of 71 patients and 68 age- and sex-matched healthy control subjects. We further performed haemostasis and platelet depletion tests in the R6/2 HD mouse model.ResultsOur findings indicate that the platelets in HD are dysfunctional with respect to the release of angiogenic factors and functions including thrombosis, angiogenesis and vascular haemostasis.ConclusionTaken together, our results provide a better understanding for the impact of mHtt on platelet function.

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Leptin Effects on the Regenerative Capacity of Human Periodontal Cells

International Journal of Endocrinology ◽

10.1155/2014/180304 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 24

Author(s):

Marjan Nokhbehsaim ◽

Sema Keser ◽

Andressa Vilas Boas Nogueira ◽

Andreas Jäger ◽

Søren Jepsen ◽

...

Keyword(s):

Adipose Tissue ◽

Periodontal Ligament ◽

Bioactive Molecules ◽

Regenerative Capacity ◽

Endocrine Organ ◽

Pdl Cells ◽

Underlying Mechanisms ◽

The Impact ◽

Periodontal Healing ◽

Local Expression

Obesity is increasing throughout the globe and characterized by excess adipose tissue, which represents a complex endocrine organ. Adipose tissue secrets bioactive molecules called adipokines, which act at endocrine, paracrine, and autocrine levels. Obesity has recently been shown to be associated with periodontitis, a disease characterized by the irreversible destruction of the tooth-supporting tissues, that is, periodontium, and also with compromised periodontal healing. Although the underlying mechanisms for these associations are not clear yet, increased levels of proinflammatory adipokines, such as leptin, as found in obese individuals, might be a critical pathomechanistic link. The objective of this study was to examine the impact of leptin on the regenerative capacity of human periodontal ligament (PDL) cells and also to study the local leptin production by these cells. Leptin caused a significant downregulation of growth (TGFβ1, and VEGFA) and transcription (RUNX2) factors as well as matrix molecules (collagen, and periostin) and inhibited SMAD signaling under regenerative conditions. Moreover, the local expression of leptin and its full-length receptor was significantly downregulated by inflammatory, microbial, and biomechanical signals. This study demonstrates that the hormone leptin negatively interferes with the regenerative capacity of PDL cells, suggesting leptin as a pathomechanistic link between obesity and compromised periodontal healing.

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Cell-type heterogeneity in adipose tissue is associated with complex traits and reveals disease-relevant cell-specific eQTLs

10.1101/283929 ◽

2018 ◽

Cited By ~ 4

Author(s):

Craig A. Glastonbury ◽

Alexessander Couto Alves ◽

Julia S. El-Sayed Moustafa ◽

Kerrin S. Small

Keyword(s):

Adipose Tissue ◽

Complex Traits ◽

Positive Association ◽

Population Level ◽

Fat Distribution ◽

Cell Types ◽

Cellular Heterogeneity ◽

Tissue Cell ◽

Cell Type ◽

The Impact

AbstractAdipose tissue is comprised of a heterogeneous collection of cell-types which can differentially impact disease phenotypes. We investigated cell-type heterogeneity in two population-level subcutaneous adipose tissue RNAseq datasets (TwinsUK, N =766 and GTEx, N=326). We find that adipose cell-type composition is heritable and confirm the positive association between macrophage proportion and obesity (BMI), but find a stronger BMI-independent association with DXA-derived body-fat distribution traits. Cellular heterogeneity can confound ‘omic analyses, but is rarely taken into account in analysis of solid-tissue transcriptomes. We benchmark the impact of adipose tissue cell-composition on a range of standard analyses, including phenotypegene expression association, co-expression networks and cis-eQTL discovery. We applied G x Cell Type Proportion interaction models to identify 26 cell-type specific eQTLs in 20 genes, including 4 autoimmune disease GWAS loci, demonstrating the potential of in silico deconvolution of bulk tissue to identify cell-type restricted regulatory variants.

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Crosstalk between Breast Cancer Cells and Bone Marrow Endothelium Require the Engagement of PI3K/AKT Signaling.

Blood ◽

10.1182/blood.v104.11.1299.1299 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1299-1299

Author(s):

Joana G. Brandao ◽

Joao T. Barata ◽

Raquel Nunes ◽

Lee M. Nadler ◽

Angelo A. Cardoso

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Endothelial Cells ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Critical Role ◽

Metastatic Breast ◽

Cell Types ◽

Akt Pathway ◽

The Impact

Abstract The presence of breast cancer cells in the patient’s bone marrow (BM) at diagnosis is associated with resistance to treatment, disease relapse and poor prognosis. Identification of the factors implicated in the homing, survival and latency of breast cancer cells in the BM should contribute to the design of more efficient therapeutic strategies for breast cancer. There is evidence that breast cancer can recruit endothelial progenitors from the BM. Also, other epithelial tumors seem to preferentially adhere to BM endothelial cells. Therefore, we hypothesized that BM endothelium may play a significant role in the biology of breast cancer cells residing in the BM. Co-cultures in Matrigel showed that breast cancer cells interact with BM endothelium to form heterotypic multicellular networks. Moreover, breast cancer cells migrate towards BM endothelium assembled as capillary-like structures, but not to structures of BM mesenchymal stem cells or BM stroma. This migration was abrogated by pertussis toxin-mediated blockade of chemokine receptor signaling, suggesting the involvement of endothelium-secreted chemokine(s). We then evaluated the impact of breast cancer cells in the survival and proliferation of BM endothelium. All breast cancer lines tested (n=4) promoted the proliferation of BM-derived endothelial cells. This effect is mediated through the engagement of the PI3K/Akt pathway (phosphorylation of Akt at Ser437 and Thr308, and activation of its downstream substrates GSK3β, PRAS-40 and FKHRL1) since its specific blockade abrogated the stimulatory effects of breast cancer on BM endothelium. We next determined whether, reciprocally, BM endothelium impacts on breast cancer cell survival. These experiments were performed in serum-free media to enhance dependency of breast cancer cells from microenvironmental stimuli. In all cases tested, BM endothelium promoted survival/proliferation of breast cancer cells. This stimulation was accompanied by the engagement of the PI3K/Akt pathway in breast cancer cells and, in three of the four lines, the phosphorylation of Erk1/2. These effects were also observed for breast cancer cells that showed constitutive activation of Akt (MCF-7 and ZR-75-1 cells). Specific blockade of PI3K/Akt abrogated the BM endothelium-promoted survival of breast cancer cells, thus demonstrating the critical role of this pathway. These studies show that crosstalk between BM endothelial cells and breast cancer cells may impact on the survival of both cell types. These findings provide new light on the mechanisms that may facilitate the development of a tumor-permissive BM microenvironment in breast cancer, and the creation of breast cancer-supporting BM niches. Importantly, this study implicates BM endothelium as a therapeutic target in breast cancer and suggest that blockade of PI3K/Akt may impact the outcome of patients with metastatic breast cancer.

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