A microarray analysis of the hypoxia-induced modulation of gene expression in human adipocytes

Mazzatti, Dawn J.; Lim, Fei Ling; O’Hara, Adrian; Wood, I. Stuart; Trayhurn, Paul

doi:10.3109/13813455.2012.654611

Cited by 62 publications

(62 citation statements)

References 44 publications

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“…The commonly used, or protein, name rather than the gene name is given for clarity. strongly upregulated in adipocytes by hypoxia (56,126). This represents, of course, a well-recognized cellular response to low O 2 tension, reflecting a switch from aerobic to anaerobic metabolism.…”

Section: A Glucose Utilizationmentioning

confidence: 97%

“…In a study from the author's group with adipocytes derived from fibroblastic preadipocytes from normal subjects and employing stringent inclusion criteria in the arrays (Ͼ2.0-fold change in mRNA level, P Ͻ 0.01), as many as ϳ1,300 genes were found to be differentially expressed in response to hypoxia (1% O 2 for 24 h) (126). Of these, half were upregulated (including LEP, IL6, and VEGF) and 650 downregulated (including ADIPOQ and UCP2).…”

Section: Hypoxia and Global Gene Expressionmentioning

confidence: 99%

“…Bioinformatic analysis indicated that several pathways and functions are modulated by hypoxia, including glucose utilization, lipid oxidation, and cell death. Network analysis points to a marked downregulation of PGC-1␣ and p38/ mitogen-activated protein kinase (MAPK) signaling in the adipocytes (126).…”

Section: Hypoxia and Global Gene Expressionmentioning

confidence: 99%

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Hypoxia and Adipose Tissue Function and Dysfunction in Obesity

Trayhurn

2013

Physiological Reviews

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686

539

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The rise in the incidence of obesity has led to a major interest in the biology of white adipose tissue. The tissue is a major endocrine and signaling organ, with adipocytes, the characteristic cell type, secreting a multiplicity of protein factors, the adipokines. Increases in the secretion of a number of adipokines occur in obesity, underpinning inflammation in white adipose tissue and the development of obesity-associated diseases. There is substantial evidence, particularly from animal studies, that hypoxia develops in adipose tissue as the tissue mass expands, and the reduction in Po2is considered to underlie the inflammatory response. Exposure of white adipocytes to hypoxic conditions in culture induces changes in the expression of >1,000 genes. The secretion of a number of inflammation-related adipokines is upregulated by hypoxia, and there is a switch from oxidative metabolism to anaerobic glycolysis. Glucose utilization is increased in hypoxic adipocytes with corresponding increases in lactate production. Importantly, hypoxia induces insulin resistance in fat cells and leads to the development of adipose tissue fibrosis. Many of the responses of adipocytes to hypoxia are initiated at Po2levels above the normal physiological range for adipose tissue. The other cell types within the tissue also respond to hypoxia, with the differentiation of preadipocytes to adipocytes being inhibited and preadipocytes being transformed into leptin-secreting cells. Overall, hypoxia has pervasive effects on the function of adipocytes and appears to be a key factor in adipose tissue dysfunction in obesity.

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Section: A Glucose Utilizationmentioning

confidence: 97%

Section: Hypoxia and Global Gene Expressionmentioning

confidence: 99%

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Hypoxia and Adipose Tissue Function and Dysfunction in Obesity

Trayhurn

2013

Physiological Reviews

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686

539

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“…However, following a 24 h incubation in either hypoxic (1%) or normoxic (21%) conditions, no differences in SEMA3C protein levels were observed in conditioned media from human adipocytes (cohort 11, data not shown). Additionally, in a recently published microarray study performed in human adipocytes [32], incubation under hypoxic conditions had no effect on SEMA3C expression, although SEMA3A expression was inhibited (2.9-fold reduction in mRNA level over 24 h).…”

Section: Sema3c Is a Novel Adipokine Predominantly Expressed In Fat Cmentioning

confidence: 99%

Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

et al. 2013

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Aims/hypothesis Alterations in white adipose tissue (WAT) function, including changes in protein (adipokine) secretion and extracellular matrix (ECM) composition, promote an insulin-resistant state. We set out to identify novel adipokines regulated by body fat mass in human subcutaneous WAT with potential roles in adipose function. Methods Adipose transcriptome data and secretome profiles from conditions with increased/decreased WAT mass were combined. WAT donors were predominantly women. In vitro effects were assessed using recombinant protein. Results were confirmed by quantitative PCR/ELISA, metabolic assays and immunochemistry in human WAT and adipocytes. Results We identified a hitherto uncharacterised adipokine, semaphorin 3C (SEMA3C), the expression of which correlated significantly with body weight, insulin resistance (HOMA of insulin resistance [HOMA IR ], and the rate constant for the insulin tolerance test [K ITT ]) and adipose tissue morphology (hypertrophy vs hyperplasia). SEMA3C was primarily found in mature adipocytes and had no direct effect on human adipocyte differentiation, lipolysis, glucose transport or the expression of β-oxidation genes. This could in part Electronic supplementary material The online version of this article

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“…VEGF protein and RNA expression in LMET and HMET cells was evaluated under normoxic and hypoxic conditions. Interleukin (IL)-6 mRNA expression was used as an additional control of hypoxic inducibility (16,17). Results presented in Fig.…”

Section: Vegf Expression Is Increased In Metastatic Hmet Cells Indepementioning

confidence: 99%

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

Čamaj

Jäckel

Krebs

et al. 2014

Molecular Cancer Research

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Pancreatic cancer aggressiveness is characterized by its high capacity for local invasion, ability to promote angiogenesis, and potential to metastasize. Hypoxia is known to represent a crucial step in the development of aggressive malignant features of many human cancers. However, micrometastatic tumors are not typically subjected to hypoxic events during early stages of dissemination; therefore, it is unclear how these tumors are able to maintain their aggressive phenotype. Thus, the identification of regulators of hypoxia-related genes in aggressive/ metastatic tumors represents a fundamental step for the design of future therapies to treat pancreatic cancer. To this end, transcriptomic profiles were compared between the nonmetastatic pancreatic cancer cell line FG (LMET) and its angiogenic/metastatic derivate L3.6pl (HMET) under normoxic or hypoxic conditions. Cluster analysis revealed a number of transcripts that were induced by hypoxia in nonmetastatic cancer cells. Strikingly, this cluster was determined to be constitutively activated under normoxia in the metastatic cancer cells and could not be further induced by hypoxia. A subset of these transcripts were regulated by the transcription factor SOX9 in the aggressivemetastatic cells, but driven by hypoxia-inducible factor-1a (HIF-1a) in the parental nonmetastatic cell line. Moreover, these transcripts were enriched in cancer-related networks including: WNT, CXCR4, retinoic acid, and (FAK) focal adhesion kinase, gene PTK2 signaling pathways. In functional assays, inhibition of SOX9 expression in HMET cells led to increased apoptosis and reduced migration in vitro and a significant reduction in primary tumor growth, angiogenesis, and metastasis following orthotopic tumor cell injection. At the molecular level, the control of SOX9 expression was associated with changes in the methylation status of the SOX9 promoter. Finally, SOX9 upregulation was verified in a series of tumor specimens of patients with pancreatic carcinoma.

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A microarray analysis of the hypoxia-induced modulation of gene expression in human adipocytes

Cited by 62 publications

References 44 publications

Hypoxia and Adipose Tissue Function and Dysfunction in Obesity

Hypoxia and Adipose Tissue Function and Dysfunction in Obesity

Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

Hypoxia-Independent Gene Expression Mediated by SOX9 Promotes Aggressive Pancreatic Tumor Biology

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