title: Cortistatin Is a Key Factor Regulating the Sex-Dependent Response of the GH and Stress Axes to Fasting in Mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: José
authors.initials: J
authors.lastname: Cordoba-Chacón
authors.affiliation: 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.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.affiliation: 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.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Pozo-Salas
authors.affiliation: 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.
authors.forename: Luis
authors.initials: L
authors.lastname: de Lecea
authors.affiliation: 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.
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
authors.affiliation: 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.
authors.forename: Raúl M
authors.initials: RM
authors.lastname: Luque
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D005215:Fasting / Q000378:metabolism*; D005260:Female; D054439:Ghrelin / Q000097:blood; D013006:Growth Hormone / Q000097:blood; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D012737:Sex Factors; D013312:Stress, Physiological / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D054439:Ghrelin; D007328:Insulin; D020738:Leptin; D009479:Neuropeptides; C099323:cortistatin; D000324:Adrenocorticotropic Hormone; D013006:Growth Hormone; D003345:Corticosterone