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1 Medicine/Cardiovascular Medicine, Stanford University, Stanford, California, United States
2 Medicine/Cardiovascular Medicine, Stanford University, 94305, California, United States; Medicine/Cardiovascular Medicine, Stanford University, Stanford, California, United States
3 Cardiovascular Surgery, Stanford University, 94305, California, United States; Medicine/Cardiovascular Medicine, Stanford University, Stanford, California, United States
4 Medicine/Cardiovascular Medicine, Stanford University, 94305, California, United States; Stanford, United States; Medicine/Cardiovascular Medicine, Stanford University, Stanford, California, United States
5 Radiation Oncology, Stanford University, Stanford, California, United States
* To whom correspondence should be addressed. E-mail: pyue{at}stanford.edu.
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. 3T3L1 cells were differentiated into adipocytes in culture. For experiments, serum starved 3T3L1 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 3T3L1 adipocytes was increased significantly by insulin, and was attenuated by pharmacologic 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 3T3L1 adipocytes and differentiated MEFs, HIF-1 appears to be involved in hypoxia- and insulin-induced apelin expression.
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