Somatostatin (SST) and cortistatin (CORT) are two highly related neuropeptides involved in the regulation of several endocrine secretions. In particular, SST and CORT are two primary negative regulators of GH secretion. Consequently, SST or CORT knockout (KO) mice exhibit elevated GH levels; however, this does not lead to increased IGF-I levels or somatic growth, which has been suggested that could be due to a compensatory mechanism between both peptides. In order to test this hypothesis, this study was designed to explore, for the first time, the consequences of simultaneously deleting endogenous SST and CORT by generating a double SST/CORT KO mouse model and exploring its endocrine and metabolic phenotype. Our results demonstrate that simultaneous deletion of SST and CORT induces a drastic elevation of endogenous GH levels, which, surprisingly, does not lead to increased growth rate or IGF-I levels, suggesting the existence of additional factors/systems that, in the absence of endogenous SST and CORT, could counteract GH-actions. Notably, elevation in circulating GH levels are not accompanied by changes in pituitary GH expression or by alterations in the expression of its main regulators (GHRH and ghrelin) or their receptors (GHRH-R, GHS-R or SST/CORT receptors) at the hypothalamic or pituitary level. However, although double SST/CORT KO male mice exhibit normal glucose and insulin levels, they have improved insulin sensitivity compared to control mice. Therefore, these results suggest the existence of an intricate interplay among the known (SST/CORT), and likely unknown, inhibitory components of the GH/IGF-I axis to regulate somatic growth and glucose/insulin homeostasis.
Funding: This work was supported by Junta de Andalucía (CTS-1406, BIO-0139, PI-0639-2012) Ministerio de Economía y Competitividad, Gobierno de España (BFU2013-43282-R), Instituto de Salud Carlos III (PI13/00651), Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn) and Ayuda Merck Serono 2013.
16 - 20 May 2015
European Society of Endocrinology