Mini-ghrelins: Functional Characterization of N-terminal Peptides Derived From Ghrelin Proteolysis in Male Samples

Le résumé fourni par la source

Some evidence suggests that ghrelin in plasma undergoes proteolytic processing, leading to the generation of shorter peptides containing the bioactive N-terminal end of this peptide hormone. However, the chemical nature and bioactivity of these shorter versions of ghrelin (termed mini-ghrelins) remain to be clearly defined. Mini-ghrelins generated in plasma were analyzed using mass spectrometry. The binding to and action on the GH secretagogue receptor (GHSR) of mini-ghrelins were assessed in vitro in a heterologous expression system using fluorescent imaging and electrophysiology, as well as in vivo in male mice through binding studies, immunohistochemistry, and behavioral assessments. We present the first characterization of peptides derived from ghrelin proteolysis in human, rat, and mouse plasma. We found that the shortest mini-ghrelin in humans and rats is ghrelin(1-11). In vitro, ghrelin(1-11) binds to GHSR, activates it with similar potency to ghrelin, and inhibits further ghrelin binding. In mice, ghrelin(1-11) binds to GHSR in orexigenic neurons of the arcuate nucleus but does not induce detectable changes in food intake or in the levels of the neuronal activation marker c-Fos in the hypothalamus. Instead, it prevents binding of fluorescent ghrelin and blocks its orexigenic effects. Ghrelin(1-14), the shortest mini-ghrelin detected in mice, exhibits similar properties to ghrelin(1-11) both in vitro and in vivo. We propose that ghrelin proteolysis in plasma-and the resulting generation of mini-ghrelins-is not merely a mechanism to reduce plasma ghrelin concentration but also a process that diminishes ghrelin's action by blocking its effects.

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