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Endocrinology. 2016 Jul;157(7):2810-23. doi: 10.1210/en.2016-1195. Epub 2016 May 13.

Cortistatin Is a Key Factor Regulating the Sex-Dependent Response of the GH and Stress Axes to Fasting in Mice.

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Maimonides Institute of Biomedical Research of Cordoba (J.C.-C., M.D.G., A.I.P.-S., J.P.C., R.M.L.); Department of Cell Biology, Physiology, and Immunology (J.C.-C., M.D.G., A.I.P.-S., J.P.C., R.M.L.), University of Córdoba; Hospital Universitario Reina Sofía (J.C.-C., M.D.G., A.I.P.-S., J.P.C., R.M.L.), Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (J.C.-C., M.D.G., A.I.P.-S., J.P.C., R.M.L.); and Campus de Excelencia Internacional Agroalimentario (J.C.-C., M.D.G., A.I.P.-S., J.P.C., R.M.L.), Córdoba 14004, Spain; Department of Medicine (J.C.-C.), Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago and Jesse Brown Veteran Affairs Medical Center, Research and Development Division, Chicago, Illinois 60612; and Department of Psychiatry and Behavioral Sciences (L.d.L.), Stanford University School of Medicine, Palo Alto, California 94305.


Cortistatin (CORT) shares high structural and functional similarities with somatostatin (SST) but displays unique sex-dependent pituitary actions. Indeed, although female CORT-knockout (CORT-KO) mice exhibit enhanced GH expression/secretion, Proopiomelanocortin expression, and circulating ACTH/corticosterone/ghrelin levels, male CORT-KO mice only display increased plasma GH/corticosterone levels. Changes in peripheral ghrelin and SST (rather than hypothalamic levels) seem to regulate GH/ACTH axes in CORT-KOs under fed conditions. Because changes in GH/ACTH axes during fasting provide important adaptive mechanisms, we sought to determine whether CORT absence influences GH/ACTH axes during fasting. Accordingly, fed and fasted male/female CORT-KO were compared with littermate controls. Fasting increased circulating GH levels in male/female controls but not in CORT-KO, suggesting that CORT can be a relevant regulator of GH secretion during fasting. However, GH levels were already higher in CORT-KO than in controls in fed state, which might preclude a further elevation in GH levels. Interestingly, although fasting-induced pituitary GH expression was elevated in both male/female controls, GH expression only increased in fasted female CORT-KOs, likely owing to specific changes observed in key factors controlling somatotrope responsiveness (ie, circulating ghrelin and IGF-1, and pituitary GHRH and ghrelin receptor expression). Fasting increased corticosterone levels in control and, most prominently, in CORT-KO mice, which might be associated with a desensitization to SST signaling and to an augmentation in CRH and ghrelin-signaling regulating corticotrope function. Altogether, these results provide compelling evidence that CORT plays a key, sex-dependent role in the regulation of the GH/ACTH axes in response to fasting.

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