Obesity- and gender-dependent role of endogenous somatostatin and cortistatin in the regulation of endocrine and metabolic homeostasis in mice.

Raúl M Luque,José Cordoba-Chacon,Luis De Lecea,Rubén Nogueiras,Justo P Castaño,Manuel D Gahete,Ana I Pozo-Salas,Begoña Porteiro

doi:10.1038/srep37992

Abstract

Somatostatin (SST) and cortistatin (CORT) regulate numerous endocrine secretions and their absence [knockout (KO)-models] causes important endocrine-metabolic alterations, including pituitary dysregulations. We have demonstrated that the metabolic phenotype of single or combined SST/CORT KO-models is not drastically altered under normal conditions. However, the biological actions of SST/CORT are conditioned by the metabolic-status (e.g. obesity). Therefore, we used male/female SST- and CORT-KO mice fed low-fat (LF) or high-fat (HF) diet to explore the interplay between SST/CORT and obesity in the control of relevant pituitary-axes and whole-body metabolism. Our results showed that the SST/CORT role in the control of GH/prolactin secretions is maintained under LF- and HF-diet conditions as SST-KOs presented higher GH/prolactin-levels, while CORT-KOs displayed higher GH- and lower prolactin-levels than controls under both diets. Moreover, the impact of lack of SST/CORT on the metabolic-function was gender- and diet-dependent. Particularly, SST-KOs were more sensitive to HF-diet, exhibiting altered growth and body-composition (fat/lean percentage) and impaired glucose/insulin-metabolism, especially in males. Conversely, only males CORT-KO under LF-diet conditions exhibited significant alterations, displaying higher glucose-levels and insulin-resistance. Altogether, these data demonstrate a tight interplay between SST/CORT-axis and the metabolic status in the control of endocrine/metabolic functions and unveil a clear dissociation of SST/CORT roles.

Highlights

Somatostatin (SST) and cortistatin (CORT) are two closely related neuropeptides that share high structural, pharmacological and functional similarities[1,2]
SST and CORT actions might be dependent on, or influenced by specific endocrine/metabolic conditions, like obesity[13,24,25,26,27], which may suggest that the final biological actions of SST and CORT may be conditioned by the specific metabolic status
Under high-fat diet (HF)-diet conditions, male SST-KO exhibited increased body weight (BW) gain compared to controls (Fig. 1B), while female SST-KO and CORT-KO male and female did not show differences (Fig. 1A,B)

Summary

Introduction

Somatostatin (SST) and cortistatin (CORT) are two closely related neuropeptides that share high structural, pharmacological and functional similarities[1,2]. Metabolic sibling of SST; recent evidence demonstrated that CORT is able to trigger unique, and even opposite, endocrine and non-endocrine actions from those exerted by SST, including the regulation of endocrine secretions, the control of immune response or the modulation of neuronal activity[2,9,12,13,14,15,16,17,18,19,20]. The present study has been conceived to unveil, for the first time, the putative interplay between SST or CORT and an extreme metabolic situation such as diet-induced obesity in the control of the most relevant pituitary hormonal axes and the whole-body metabolic function by using male and female SST- and CORT-KO mice fed a low-fat or a high-fat diet and, their respective lean and obese littermate controls

Methods

Results

Conclusion