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This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/E1590    most recent 00490.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Glassford, A. J. Articles by Tsao, P. S. PubMed PubMed Citation Articles by Glassford, A. J. Articles by Tsao, P. S.

HIF-1 regulates hypoxia- and insulin-induced expression of apelin in adipocytes

¹Division of Cardiovascular Medicine, Department of Medicine; ²Department of Cardiothoracic Surgery; and ³Department of Radiation Oncology, Stanford University Medical Center, Stanford, California

Submitted 27 July 2007 ; accepted in final form 17 September 2007

Apelin, a novel peptide with significant cardioactive properties, is upregulated by insulin in adipocytes. However, the mechanism by which insulin promotes apelin production is unknown. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor involved in the angiogenic and metabolic responses to tissue hypoxia, has been shown to be activated by insulin in various settings. We therefore hypothesized that HIF-1 regulates insulin-mediated apelin expression in adipocytes. 3T3-L1 cells were differentiated into adipocytes in culture. For experiments, serum-starved 3T3-L1 cells were exposed to insulin and/or a 1% O₂ environment. Apelin expression was assessed using quantitative real-time PCR and ELISA. To directly assess the role of HIF-1 in apelin production, we differentiated mouse embryonic fibroblasts (MEFs) containing a targeted deletion of the HIF-1 gene into adipocytes and measured their response to insulin and hypoxia. Apelin expression in mature 3T3-L1 adipocytes was increased significantly by insulin and was attenuated by pharmacological inhibition of insulin signaling. Exposure of cells to either hypoxia or the chemical HIF activators cobalt chloride (CoCl₂) and dimethyloxaloylglycine (DMOG) resulted in significant upregulation of apelin, consistent with a role for HIF in apelin induction. Moreover, hypoxia-, CoCl₂-, DMOG-, and insulin-induced apelin expression were all attenuated in differentiated HIF-1-deficient MEFs. In summary, in cultured 3T3-L1 adipocytes and differentiated MEFs, HIF-1 appears to be involved in hypoxia- and insulin-induced apelin expression.

hypoxia-inducible factor; adipocyte; obesity