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Papers In Press, published online ahead of print June 25, 2002
Molecular Biology, Institute for Diabetes Discovery, Branford, CT 06405
Corresponding Author: jfriveros{at}msn.com
Besides a major role in energy homeostasis, leptin is emerging as a pleiotropic cytokine with multiple physiological effector functions. The recently discovered proangiogenic activity of leptin suggested the hypothesis that its production might be regulated by hypoxia like other angiogenic factors. To examine this proposal, expression of leptin protein and mRNA was measured and found to be markedly upregulated in response to ambient or chemical hypoxia (upon exposure to desferrioxamine or cobalt chloride), an effect that requires intact RNA synthesis suggesting a transcriptional mechanism. Transient transfection of cultured cells with deletion constructs of the leptin gene promoter linked to a reporter gene revealed a functional hypoxia response element (HRE) located at position –116 within the proximal upstream region. This putative HRE harbors a characteristic 5’-RCGTG-3’ core motif, a hallmark of hypoxia-sensitive genes and recognized by the hypoxia inducible factor 1 (HIF1), which consists of a HIF1á/HIFb heterodimer. Constructs harboring this –116/HRE supported reporter gene expression in response to hypoxia, but not when mutated. Expression of HIF1á cDNA in normoxic cells mimicked hypoxia-induced reporter gene expression in cells cotransfected with the wild type leptin –116/HRE construct, but not with the mutant. Gel shift assays with a 32P-labeled leptin promoter –116/HRE probe and nuclear extracts from hypoxia-treated cells indicated binding of the HIF1á/b heterodimer, which was blocked with an excess of unlabeled –116/HRE probe or a HIF1-binding probe from the erythropoietin gene enhancer. Taken together, these observations demonstrate that the leptin gene is actively engaged by hypoxia through a transcriptional pathway commonly utilized by hypoxia-sensitive genes.
J. Biol. Chem, 10.1074/jbc.M205172200
Submitted on May 26, 2002
Revised on June 25, 2002
Accepted on June 25, 2002
Transcriptional activation of the human leptin gene in response to hypoxia: Involvement of hypoxia-inducible factor 1
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