Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflügers Archiv European Journal of Physiology

Obesity Biology Unit (Liverpool Centre for Nutritional Genomics and Liverpool Obesity Research Network), School of Clinical Sciences, University Clinical Departments, University of Liverpool, Liverpool, UK.
Pflügers Archiv - European Journal of Physiology (Impact Factor: 4.1). 01/2008; 455(3):479-92. DOI: 10.1007/s00424-007-0301-8
Source: PubMed


The effect of hypoxia, induced by incubation under low (1%) oxygen tension or by exposure to CoCl(2), on the expression and secretion of inflammation-related adipokines was examined in human adipocytes. Hypoxia led to a rapid and substantial increase (greater than sevenfold by 4 h of exposure to 1% O(2)) in the hypoxia-sensitive transcription factor, HIF-1alpha, in human adipocytes. This was accompanied by a major increase (up to 14-fold) in GLUT1 transporter mRNA level. Hypoxia (1% O(2) or CoCl(2)) led to a reduction (up to threefold over 24 h) in adiponectin and haptoglobin mRNA levels; adiponectin secretion also decreased. No changes were observed in TNFalpha expression. In contrast, hypoxia resulted in substantial increases in FIAF/angiopoietin-like protein 4, IL-6, leptin, MIF, PAI-1 and vascular endothelial growth factor (VEGF) mRNA levels. The largest increases were with FIAF (maximum 210-fold), leptin (maximum 29-fold) and VEGF (maximum 23-fold); these were reversed on return to normoxia. The secretion of IL-6, leptin, MIF and VEGF from the adipocytes was also stimulated by exposure to 1% O(2). These results demonstrate that hypoxia induces extensive changes in human adipocytes in the expression and release of inflammation-related adipokines. Hypoxia may underlie the development of the inflammatory response in adipocytes, leading to obesity-associated diseases.

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    • "The CoCl2 method has the advantage of being fast and inexpensive and provides a more stable hypoxia that is not possible with hypoxic chambers (Wu and Yotnda 2011). Our experiments show typical hypoxia response genes such as hypoxia inducible factor 1 α (HIF1a), vascular endothelial growth factor A (VEGFA), and glucose transporter 1 (GLUT1) to be over expressed in hypoxia induced by CoCl2 (data submitted to GEO database), making our results comparable to low O2 tension experiments (Liu et al. 1999; Wang et al. 2007). "
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    ABSTRACT: Human umbilical vein endothelial cell (HUVEC)-based gene expression studies carried out under hypoxia and/ or hyperglycemia bear huge potential in modelling endothelial cell response in cardiovascular disease and diabetes. However, such studies require reference genes that are stable across the whole range of experimental conditions. These reference genes have not been comprehensively defined to date. We applied human genome-wide microarrays and quantitative real-time PCR (qRT-PCR) on RNA obtained from primary HUVEC cultures that were incubated for 24 h either in euglycemic or hyperglycemic conditions and then subjected to short-term CoCl2-induced hypoxia of either 1, 3 or 12 h. Using whole-transcript arrays, we selected ten commonly used reference genes with no significant expression variation across 8 different conditions. These genes were ranked using NormFinder software according to their stability values. Consequently, five genes were selected for validation by quantitative real-time PCR (qRT-PCR). These were: ribosomal protein large P0 (RPLP0), transferrin receptor (TFRC), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), β-glucuronidase (GUSB), and β-actin (ACTB). All five genes displayed stable expression under hyperglycemia. However, only RPLP0 and TFRC genes were stable under hypoxia up to 12 h. Under hyperglycemia combined with hypoxia up to 12 hours the expression of RPLP0, TFRC, GUSB and ACTB genes remained unchanged. Our findings strongly confirm that RPLP0 and TFRC are the most suitable reference genes for HUVEC gene expression experiments subjected to hypoxia and/or hyperglycemia for the given experimental conditions. We provide further evidence that even commonly known references genes require experimental validation for all conditions involved.
    G3-Genes Genomes Genetics 09/2014; 4(11). DOI:10.1534/g3.114.013102 · 3.20 Impact Factor
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    • "More and more evidence has reported the contribution made by HIFs to MS. Hyperplasia and hypertrophy of adipocytes may lead to local hypoxia, which subsequently upregulates HIF expression and augments macrophage infiltration [77]. In cultured adipocytes and preadipocytes, overexpression of HIF-1α was also detected when the cells were exposed to hypoxia [78]. Hyperglycemia interferes with HIF-1α stabilization, although the mechanisms are not well-defined. "
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    ABSTRACT: Background Metabolic syndrome (MS) is a cluster of metabolic abnormalities, which has been regarded as a pivotal risk factor for cardiovascular diseases. Recent studies focusing on the relationship between MS and cancer have recognized the significant role of MS on carcinogenesis. Likewise, growing evidence suggests that MS has a strong association with increased renal cell carcinoma (RCC) risk. This review outlines the link between MS and RCC, and some underlying mechanisms responsible for MS-associated RCC. Materials and methods A National Center for Biotechnology Information PubMed search ( was conducted using medical subject headings ‘metabolic syndrome’, ‘obesity’, ‘hypertension’, ‘diabetes’, ‘dyslipidemia’, and ‘renal cell carcinoma’. Results This revealed that a variety of molecular mechanisms secondary to MS are involved in RCC formation, progression, and metastasis. A deeper understanding of these molecular mechanisms may provide some strategies for the prevention and treatment of RCC. Conclusions In summary, there is a large body of evidence regarding the link between MS and RCC, within which each component of MS is considered to have a close causal association with RCC.
    World Journal of Surgical Oncology 07/2014; 12(1):236. DOI:10.1186/1477-7819-12-236 · 1.41 Impact Factor
    • "As with other body tissues this contributes to cellular and organ dysfunction [16] and pro-inflammatory responses, all contributing to metabolic disease [17]. Cell culture studies using murine and human adipocytes strongly support the modulatory role of hypoxia in the production of several pro-inflammatory adipokines [18]. Even modest changes in oxygen levels induce specific changes in gene expression and metabolism of human adipocytes [19]. "
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    ABSTRACT: Adipocytes are no longer considered just as cells related to storage of energy and thermoregulation. Now we know that they release a huge number of paracrine and endocrine biologically active molecules. This is also the case for perivascular adipose tissue (PVAT) that surrounds almost all blood vessels in the organism. PVAT secretes the so-called adipo(cyto)kines that, because of its proximity, can easily influence vascular smooth muscle cells. The role of PVAT on vascular function can be both protective and deleterious. Normal healthy PVAT, as present in lean subjects, helps to keep the blood vessels dilated as its presence diminishes the effect of vasocontractile agents. Obesity is associated with an increased mass in PVAT. Excessive adipocyte hypertrophy may result in "adiposopathy" in which PVAT attracts macrophages and becomes a more inflammatory phenotype. This leads to a change in profile of the released adipo(cyto)kines, resulting in a decreased vasorelaxing effect of PVAT, which may be linked to obesity-induced hypertension. It also results in smooth muscle cell migration and proliferation and the development of atherosclerotic lesions. The increased knowledge of PVAT function brings up new targets that can be useful to develop novel therapeutic and preventive strategies for obesity-related cardiovascular diseases. This mini-review presents a general overview of the actual knowledge on the role of PVAT on vascular function and dysfunction in obesity.
    Current Vascular Pharmacology 05/2014; 12(3):403-11. DOI:10.2174/1570161112666140423220628 · 2.97 Impact Factor
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