title: Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels.
abstract: Somatostatin (SST) and cortistatin (CORT) are two highly related neuropeptides involved in the regulation of various endocrine secretions. In particular, SST and CORT are two primary negative regulators of GH secretion. Consequently, single SST or CORT knockout mice exhibit elevated GH levels; however, this does not lead to increased IGF-1 levels or somatic growth. This apparent lack of correspondence has been suggested to result from compensatory mechanisms between both peptides. To test this hypothesis, in this study we explored, for the first time, the consequences of simultaneously deleting endogenous SST and CORT by generating a double SST/CORT knockout mouse model and exploring its endocrine and metabolic phenotype. Our results demonstrate that simultaneous deletion of SST and CORT induced a drastic elevation of endogenous GH levels, which, surprisingly, did not lead to changes in growth rate or IGF-1 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 were 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 receptor, GHS receptor, or SST/CORT receptors) at the hypothalamic or pituitary level. However, although double-SST/CORT knockout male mice exhibited normal glucose and insulin levels, they had improved insulin sensitivity compared with the 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-1 axis to regulate somatic growth and glucose/insulin homeostasis.
authors.affiliation: Department of Cell Biology, Physiology, and Immunology (S.P.-A., J.C.-C., A.I.P.-S., F.L.L., M.D.G., J.P.C., R.M.L.), University of Córdoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, and Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERObn), E-14014 Córdoba, Spain; Section of Endocrinology, Diabetes, and Metabolism (J.C.-C.), Department of Medicine (J.C.-C.), University of Illinois at Chicago, Chicago, Illinois 60637; Department of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612; and Department of Psychiatry and Behavioral Sciences (L.d.L.), Stanford University, Stanford, California 94305.
authors.forename: S
authors.initials: S
authors.lastname: Pedraza-Arévalo
authors.forename: J
authors.initials: J
authors.lastname: Córdoba-Chacón
authors.forename: A I
authors.initials: AI
authors.lastname: Pozo-Salas
authors.forename: F
authors.initials: F
authors.lastname: L-López
authors.forename: L
authors.initials: L
authors.lastname: de Lecea
authors.forename: M D
authors.initials: MD
authors.lastname: Gahete
authors.forename: J P
authors.initials: JP
authors.lastname: Castaño
authors.forename: R M
authors.initials: RM
authors.lastname: Luque
mesh_terms: D000818:Animals; D005260:Female; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D013004:Somatostatin / Q000627:therapeutic use*
chemical_list: D009479:Neuropeptides; C099323:cortistatin; D013004:Somatostatin; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone