Obestatin plays an opposite role in the regulation of pituitary somatotrope and corticotrope function in female primates and male/female mice.

Obestatin is a 23 amino acid, amidated-peptide that is encoded by the ghrelin gene. Previous studies have shown obestatin can modulate the hypothalamic neuronal circuitry that regulates pituitary function, perhaps by modulating the actions of ghrelin. However, the direct actions of obestatin on pituitary function remain controversial. Here, primary pituitary cell cultures from a non-human primate (baboon) and mice were used to test the effects of obestatin on pituitary hormone expression and secretion. In pituitary cultures from both species, obestatin had no effect on prolactin, LH, FSH or TSH expression/release. Conversely, obestatin stimulated POMC expression and ACTH release, and inhibited GH expression/release in vitro, actions that were also observed in vivo in mice treated with obestatin. In vitro, obestatin inhibited the stimulatory actions of ghrelin on GH but not ACTH release. The inhibitory effect of obestatin on somatotrope-function was associated with an overall reduction in pituitary Pit-1 and GHRH-R mRNA levels, in vitro and in vivo, as well as a reduction in hypothalamic GHRH and ghrelin expression, in vivo. The stimulatory effect of obestatin on ACTH was associated with an increase in pituitary CRF-receptors. Obestatin also reduced the expression of pituitary somatostatin receptors (sst1/sst2), which could serve to modify its impact on hormone secretion. The in vitro actions of obestatin on both GH and ACTH release required the adenylyl-cyclase and MAPK routes. Taken together, our results provide evidence that obestatin can act directly at the pituitary to control somatotrope- and corticotrope-function, and these effects are conserved across species.