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.2011 Dec;152(12):4800-12.
doi: 10.1210/en.2011-1542. Epub 2011 Oct 4.

Cortistatin is not a somatostatin analogue but stimulates prolactin release and inhibits GH and ACTH in a gender-dependent fashion: potential role of ghrelin

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Cortistatin is not a somatostatin analogue but stimulates prolactin release and inhibits GH and ACTH in a gender-dependent fashion: potential role of ghrelin

José Córdoba-Chacón et al. Endocrinology.2011 Dec.

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.

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Figures

Fig. 1.
Fig. 1.
Regulation of pituitary somatotrope, lactotrope, and corticotrope cell axes in male and female wild-type (cort+/+,open columns)vs. cort−/− (black columns) mice. A, Basal GH release (left), GH expression (middle), and circulating IGF-I levels (right). B, Growth curves from males and females cort+/+ (solid lines) and cort−/− (dotted line) littermates from 4 to 13 wk of age. C, Basal PRL release (left), PRL expression (middle), and percentage of survival of the first litter of female cort+/+ (open column)vs. cort−/− (solid column) mice (right). D, Basal PRL release in a second group of male and female cort+/+ (open columns) and cort−/− (black columns) as compared with male and female sst+/+ (open columns) and sst−/− (gray columns). E, Basal PRL levels in 7 d vehicle-infused (Veh) and CST14-infused (CST) female cort+/+ and cort−/− mice via sc osmotic pumps. F, Basal ACTH hormone release (left), POMC expression (middle), and circulating corticosterone levels (right). Values represent mean ±sem (six to seven mice/genotype per gender) of hormonal circulating levels or absolute hormone mRNA copy numbers (adjusted by NF). Percentages of litter survival from female mice are expressed as mean ±sem (n = 11–37 breeders).Asterisks indicate values that significantly differ from their controls (cort+/+ or sst+/+) (*,P < 0.05; **,P < 0.01; ***,P < 0.001).
Fig. 2.
Fig. 2.
Expression of pituitary components involved in the regulation of somatotrope, lactotrope, and corticotrope axes in cort−/− and cort+/+ mice. A, Expression of ghrelin, In2-ghrelin, GOAT, ghrelin receptor (GHS-R), and GHRH-R; B, Expression of SST and SST receptors isoforms/variants (sst); C, Expression of DR2, PRL-releasing hormone receptor (PRLRH-R), and CRF-R1 and CRF-R2 in male (open columns) and female (solid columns) cort−/− mice. Values are showed as relative percentage of male or female cort−/−vs. control (cort+/+) mice (shown by the dotted line set at 100%) and represent the mean ±sem of five to eight mice/gender.Asterisk (*,P < 0.05) indicates values that significantly differ from cort+/+ within gender.
Fig. 3.
Fig. 3.
Direct effect of CST or lack of endogenous CST on pituitary hormonal expression and secretion of male/female mice and female baboons. A, GH, PRL, and ACTH release levels (24-h culture; ng/ml) in primary pituitary cell cultures of male and female cort+/+ (white columns) and cort−/− (gray columns) mice under basal condition. B, Effect of CST-14 (100 nm, 24 h) on GH, PRL, POMC, LH, FSH, TSH, and GAS expression on primary pituitary cell cultures of male (white columns) and female (black columns) wild-type (cort+/+) mice. C, Effect of CST-14 (100 nm, 24 h) on GH, PRL, and ACTH release on primary pituitary cell cultures of male (white columns) and female (black columns) wild-type (cort+/+) mice. D, Effect of CST-14 (100 nm, 24 h) on SST receptors isoforms/variants (sst) on primary pituitary cell cultures of male (white columns) and female (black columns) wild-type (cort+/+) mice. E, Effect of CST-17 (100 nm, 24 h) on GH, PRL, and POMC expression (left) and on GH, PRL, and ACTH release (right) in primary pituitary cell cultures of female baboon. F, Effect of 100 nm CST-17 (in baboons; 100 nm), 1 μm CST-14, or 100 nm SST-14 (in mice) (24 h) alone or in combination with BIM-28163 (GHS-R1a antagonist; 10 nm) on PRL release in primary pituitary cell cultures of female baboon and mice [vehicle-treated control (C) was set at 100%]. Values are represented as the means ±sem of three to four independent experiments (three to five wells/treatment per genotype/gender) and in B–E are expressed as percentage of vehicle-treated controls (shown by the dotted line set at 100%).Asterisks (*,P < 0.05; **,P < 0.01; ***,P < 0.001) indicate values that differ from the corresponding controls within genders (from vehicle-treated controls for B–E and from cort+/+ within genders for A). In F, values that differ significantly (P < 0.05) are designated bydifferent letters (a and b).
Fig. 4.
Fig. 4.
Impact of lack of endogenous CST or SST in the regulation of stomach ghrelin and SST systems. A, Circulating levels of acylated and total (acylated plus nonacylated) ghrelin in male and female cort+/+ (white columns)vs. cort−/− (gray columns) mice (left) and sst+/+ (white columns)vs. sst−/− (gray columns) mice (right). B, Stomach expression of ghrelin and GOAT of male (open columns) and female (solid columns) cort+/+vs. cort−/− mice (left panel) and sst+/+vs. sst−/− mice (right panel). C, Stomach expression of SST and SST receptors isoforms/variants (sst) of male (open columns) and female (solid columns) cort+/+vs. cort−/− mice. D, Circulating SST levels in male and female cort+/+ (white columns)vs. cort−/− (gray columns) mice. Circulating hormone levels (A and D) are represented as the mean ±sem of male and female cort−/− or sst−/−vs. littermate controls (cort+/+ or sst+/+, respectively; four to 10 mice/genotype per gender). Expression levels (B and C) are showed as relative percentage of male or female cort−/−vs. control (cort+/+) mice (shown by thedotted line set at 100%) and represent the mean ±sem of five to eight mice/genotype per gender.Asterisks (*,P < 0.05; **,P < 0.01; ***,P < 0.001) indicate differences between controls (+/+) and knockout (−/−) mice within gender. n.d., Not determined; n.m., not measured.
Fig. 5.
Fig. 5.
Impact of lack of endogenous CST or SST on glucose homeostasis. Circulating insulin levels in male and female cort+/+ (white columns)vs. cort−/− (gray columns) (A) and sst+/+ (white columns)vs. sst−/− (gray columns) (D) mice. GTT (top) and ITT (bottom) of male (right) and female (left) cort+/+ (solid lines)vs. cort−/− (dotted lines) mice (B) and of male (right) and female (left) sst+/+ (solid lines)vs. sst−/− (dotted lines) mice (E). Area under curve (AUC) of GTT (top) and ITT (bottom) conducted in male and female cort+/+ (white columns)vs. cort−/− (gray columns) mice (C) and of male and female sst+/+ (white columns)vs. sst−/− (gray columns) mice (F). GTT and ITT were performed as we previously reported (26). Values are represented as the means ±sem (n = 6–12 mice/genotype per gender).Asterisks (*,P < 0.05; **,P < 0.01; ***,P < 0.001) indicate values that significantly differ from cort+/+ (A–C) or sst+/+ (D and E) within gender.
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