Cortistatin Is Not a Somatostatin Analogue but Stimulates Prolactin Release and Inhibits GH and ACTH in a Gender-Dependent Fashion: Potential Role of Ghrelin

Abstract

Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies. Although CST has been considered as a natural SST-analogue acting through their shared receptors (SST receptors 1-5), emerging evidence indicates that these peptides might in fact exert unique roles via selective receptors [e.g. CST, not SST, binds ghrelin receptor growth hormone secretagogue receptor type 1a (GHS-R1a)]. To determine whether the role of endogenous CST is different from SST, we characterized the endocrine-metabolic phenotype of male/female CST null mice (cort-/-) at hypothalamic-pituitary-systemic (pancreas-stomach-adrenal-liver) levels. Also, CST effects on hormone expression/secretion were evaluated in primary pituitary cell cultures from male/female mice and female primates (baboons). Specifically, CST exerted an unexpected stimulatory role on prolactin (PRL) secretion, because both male/female cort-/- mice had reduced PRL levels, and CST treatment (in vivo and in vitro) increased PRL secretion, which could be blocked by a GHS-R1a antagonist in vitro and likely relates to the decreased success of female cort-/- in first-litter pup care at weaning. In contrast, CST inhibited GH and adrenocorticotropin-hormone axes in a gender-dependent fashion. In addition, a rise in acylated ghrelin levels was observed in female cort-/- mice, which were associated with an increase in stomach ghrelin/ghrelin O-acyl transferase expression. Finally, CST deficit uncovered a gender-dependent role of this peptide in the regulation of glucose-insulin homeostasis, because male, but not female, cort-/- mice developed insulin resistance. The fact that these actions are not mimicked by SST and are strongly gender dependent offers new grounds to investigate the hitherto underestimated physiological relevance of CST in the regulation of physiological/metabolic processes.

Paradoxical Effect of Cortistatin Treatment and Its Deficiency on Experimental Autoimmune Encephalomyelitis

“…However, evidence indicates that cortistatin could act at multiple levels as an endogenous brake for the HPA axis. Thus, systemic injection of cortistatin decreased the levels of ACTH and cortisol in patients with Cushing disease (35), and it inhibited ACTH production in murine and monkey pituitary cultures (12), supporting a direct pituitary effect. However, the fact that cortistatin inhibited the secretion of corticotropinreleasing hormone (CRH) by tissue cultures of hypothalamus and hippocampus (36), two brain areas where CRH functions are associated with the control of endocrine HPA-mediated responses and with the pathogenesis of anxiety/depressive disorders, respectively, supports its action at these brain levels.…”

“…Characterizing the endocrine system of CST 2/2 mice, we found recently that lack of cortistatin significantly affects the functionality of the hypothalamic-pituitary-adrenal (HPA) axis (12). The systemic levels of the glucocorticoid corticosterone in CST 2/2 mice in basal conditions are markedly elevated (Fig.…”

Ghrelin gene products, receptors, and GOAT enzyme: biological and pathophysiological insight

“…However, the molecular bases underlying this interaction are still to be elucidated. Interestingly, recent studies have suggested that the GHSR, GHSR1a, is also able to mediate AG-independent PRL stimulation in response to other ligands (Cordoba-Chacon et al 2011). Specifically, cortistatin but not its related peptide, SST, is able to increase PRL secretion in mouse and baboon primary pituitary cell cultures, an effect that was completely blocked after a preincubation with a specific antagonist of the GHSR1a (Cordoba-Chacon et al 2011).…”

Truncated variants of pig somatostatin receptor subtype 5 (sst5) act as dominant-negative modulators for sst2-mediated signaling

“…In fact, SST and CORT share many actions, especially their ability to regulate the secretion of several hormones (2, 16), which seems to be determined by the capacity of both peptides to indistinguishably bind and activate all five ssts (34). However, CORT also exerts unique functions, not shared with SST, at the level of the central nervous, the immune, and even at the endocrine system, which cannot be explained by the existence of the currently known ssts (8,17,18).These and other unsolved questions associated with the SST/ CORT/receptors pathophysiology have led several authors to propose the existence of additional receptors and/or mechanisms, either related or not to the sst family to explain their findings (3,31,35). In this context, our group recently identified the existence of new truncated but functional sst5 variants in humans (13, 14) and rodents (7).…”