Abstract
Nicotinamide phosphoribosyltransferase (Nampt/visfatin/PBEF) acts both as an enzyme in the nicotinamide adenine dinucleotide (NAD) synthesis pathway as well as an extracellular hormone (eNampt). Among its effects, eNampt exerts potent pro-inflammatory effects. We have recently shown that, in rats, eNampt stimulates corticosterone secretion by acting through the pituitary rather than the hypothalamus. To investigate the mechanism of action of eNampt on the secretion of adrenocorticotropic hormone (ACTH) and chemokine (C-C motif) ligand 2 (CCL2), which are cytokines secreted by pituitary neuroendocrine tumors. The research was carried out on the AtT-20 murine cell line, primary rat pituitary cell culture, isolated pituitary corticotropes, and in vivo. The effects of the performed experiments were examined using the following methods: gene expression profiling using microarrays, quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). The results suggest that eNampt stimulates ACTH secretion from rat corticotropes both directly and indirectly. Indirect action most likely occurs through interleukin (IL)-6 secreted by folliculostellate cells of the pituitary gland. In isolated ACTH cells of the rat pituitary gland, eNampt stimulates the expression of genes involved in the immune response. Among them, the protein encoded by the CCL2 gene seems to also be involved in the regulation of corticotropin-releasing hormone (CRH)-dependent metabolism. Unlike rat corticotropes, murine AtT-20 corticotropic cells do not react to either eNampt or Fk866 (the inhibitor of Nampt enzymatic action). The eNampt stimulates the secretion of ACTH from rat corticotropes indirectly and directly, likely by stimulating IL-6 secretion from folliculostellate cells of the pituitary gland. This effect was not observed in the AtT-20 corticotropic cell cancer cell line.
Highlights
Nicotinamide phosphoribosyltransferase (Nampt/visfatin/PBEF) acts both as an enzyme in the nicotinamide adenine dinucleotide (NAD) synthesis pathway as well as an extracellular hormone
The results suggest that eNampt stimulates adrenocorticotropic hormone (ACTH) secretion from rat corticotropes both directly and indirectly
In isolated ACTH cells of the rat pituitary gland, eNampt stimulates the expression of genes involved in the immune response
Summary
Nicotinamide phosphoribosyltransferase (Nampt/visfatin/PBEF) acts both as an enzyme in the nicotinamide adenine dinucleotide (NAD) synthesis pathway as well as an extracellular hormone (eNampt). Apart from its intracellular function (iNampt), is secreted outside the cells where it circulates in the bloodstream as a hormone (eNampt), called visfatin or pre-B cell colony-enhancing factor (PBEF).[1,2,3] eNampt is secreted mainly by adipose tissue, but has been proven to be secreted by many other types of cells.[4] eNampt can be detected in the human bloodstream and other extracellular fluids, where it exerts pro-inflammatory, prochemotactic (promoting migration of the cells), proangiogenic, and insulin-like effects. The obtained results suggest that the stimulating effect of eNampt protein on corticosterone secretion in rats is dependent on the pituitary gland. The mechanism of action of eNampt on changes in the pituitary gland of rats described above remains unexplained
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