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J. Biol. Chem., Vol. 277, Issue 45, 42953-42957, November 8, 2002

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Hypoxia-inducible Factor 1 Transactivates the Human Leptin Gene Promoter^*

Alexandra Grosfeld, Jocelyne André, Sylvie Hauguel-de Mouzon^§, Edurne Berra^¶, Jacques Pouysségur^¶, and Michèle Guerre-Millo

From  INSERM U 465, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 15 Rue de l'Ecole de Médecine, 75006 Paris, France, ^§ Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, and ^¶ CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue Valombrose, 06189 Nice, France

Increased placental leptin has been demonstrated in preeclampsia, a pregnancy disorder associated with placental hypoxia. This suggests that leptin gene expression is enhanced in response to oxygen deficiency in this organ. In support of this hypothesis, we have previously shown that hypoxia activates the leptin promoter in trophoblast-derived BeWo cells. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric HIF-1/HIF-1 complex that regulates the transcription of hypoxia-responsive genes. To test whether this factor is involved in hypoxia-induced leptin promoter activation, BeWo cells were transiently transfected with a HIF-1 expression vector. Exogenous HIF-1 markedly increased luciferase reporter activity driven by the leptin promoter when HIF-1 was co-expressed in the same cells. This effect was similar to that elicited by CoCl₂, an agent known to stabilize endogenous HIF-1. These data suggest that HIF-1/HIF-1 dimers are involved in the effect of CoCl₂ to activate the leptin promoter. To confirm the implication of HIF-1, the cells were transfected with a dominant negative form of HIF-1 producing transcriptionally inactive HIF-1/HIF-1 dimers. This mutant HIF-1 protein abolished CoCl₂ activation of the leptin promoter, providing direct evidence that the effect of CoCl₂ is mediated by endogenous HIF-1. Deletion analysis and site-specific mutagenesis demonstrated that a HIF-1 consensus binding site (HRE) spanning 120 to 116 bp relative to the start site was required for CoCl₂ and exogenous HIF-1 induction of leptin promoter activity. Electrophoretic mobility shift assays performed with in vitro-translated HIF-1 and HIF-1 proteins demonstrated binding to this HRE and not to mutated sequences only when both subunits were used together. These data demonstrate that leptin is a new hypoxia-inducible gene, which is stimulated in a placental cell line through HIF-1 interaction with a consensus HRE site located at 116 in the proximal promoter.

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