High glucose activates pituitary proopiomelanocortin gene expression: possible role of free radical-sensitive transcription factors

Background Hyperglycemia is recognized as a metabolic stress, and indeed it is known to stimulate hypothalamo-pituitary-adrenal (HPA) axis, a representative anti-stress system, in patients with diabetes mellitus or in animal models of hyperglycemia. Thus, we tried to clarify the molecular mechanism of glucose-induced HPA axis activation. Methods We studied the effect of high glucose on the transcriptional regulation of proopiomelanocortin (POMC) gene that encodes adrenocorticotropic hormone, a central mediator of HPA axis, using AtT20 corticotroph cell line in vitro. Results We found that high glucose concentration (24 mm) significantly stimulated the 5'-promoter activity of POMC gene. The effect was promoter-specific, and was mimicked by nuclear factor-kappaB (NF-kappa B)- or AP1-responsive promoters but not by cAMP-responsive element or serum-response element-containing promoters. Furthermore, the stimulatory effect of high glucose on POMC gene was eliminated by NF-kappa B and AP1 inhibitors, suggesting the involvement of the transcriptional factors. The POMC 5'-promoter has the canonical NF-kappa B consensus sequence and gel shift assay, showed the binding of NF-kappa B to the element. Finally the effect of high, glucose was completely abolished by treatment with a radical quencher 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL). Conclusions Our data suggest that hyperglycernia activates POMC gene expression, at least partly, via NF-kappa B/AP1, and that high-glucose-induced free radical generation may mediate the activation of these transcription factors, which in turn stimulates the transcription of POMC gene. Copyright (C) 2006 John Wiley & Sons, Ltd.