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.
Highlights
Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies
Studies examining the effects of exogenously administered CST indicate that some, but not all, actions mimic those of SST [4, 6], information is lacking regarding the physiologic role of endogenous CST in maintaining endocrine function
Elevation in GH output in cortϪ/Ϫ mice was not associated with changes in pituitary expression of key components of pathways, which would be predicted to enhance GH release [GHRH receptor (GHRH-R), growth hormone secretagogue receptor (GHS-R), ghrelin, In2-ghrelin, and ghrelin O-acyl transferase (GOAT)] (Fig. 2A), whereas paradoxically there was a female-specific increase in pituitary expression of sst2A/ sst3/sst5/sst5TMD1 (Fig. 2B)
Summary
Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies. Studies examining the effects of exogenously administered CST indicate that some, but not all, actions mimic those of SST [4, 6], information is lacking regarding the physiologic role of endogenous CST in maintaining endocrine function To address this issue, in the present study, we characterized the hypothalamic-pituitary-systemic phenotypes of male and female CST null (cortϪ/Ϫ) mice and compared them with endocrine phenotype of SST null (sstϪ/Ϫ) mice, which has been previously reported (19 –24) or investigated in parallel with cortϪ/Ϫ in the current series of studies.
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