Pedraza-Arévalo S, Córdoba-Chacón J, Pozo-Salas A I, L-López F, de Lecea L, Gahete M D, Castaño J P, Luque R M
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.
Endocrinology. 2015 Jun;156(6):1958-64. doi: 10.1210/en.2015-1132. Epub 2015 Apr 1.
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.
生长抑素（SST）和可体松（CORT）是两种高度相关的神经肽，参与多种内分泌分泌的调节。特别是，SST和CORT是生长激素（GH）分泌的两个主要负调节因子。因此，单基因敲除SST或CORT的小鼠表现出血清GH水平升高；然而，这并未导致胰岛素样生长因子-1（IGF-1）水平升高或体细胞生长增加。有人认为这种明显的不一致是由于这两种肽之间的代偿机制所致。为了验证这一假设，在本研究中，我们首次通过构建双基因敲除SST/CORT小鼠模型并探索其内分泌和代谢表型，研究了同时缺失内源性SST和CORT的后果。我们的结果表明，同时缺失SST和CORT会导致内源性GH水平急剧升高，令人惊讶的是，这并未导致生长速率或IGF-1水平发生变化，这表明存在其他因素/系统，在缺乏内源性SST和CORT的情况下，这些因素/系统可以抵消GH的作用。值得注意的是，循环GH水平的升高并未伴随着垂体GH表达的变化，也未伴随着下丘脑或垂体水平上其主要调节因子（生长激素释放激素（GHRH）和胃饥饿素）或其受体（GHRH受体、生长激素促分泌素受体或SST/CORT受体）表达水平的改变。然而，尽管双基因敲除SST/CORT的雄性小鼠血糖和胰岛素水平正常，但与对照小鼠相比，它们的胰岛素敏感性有所提高。因此，这些结果表明，在已知的（SST/CORT）以及可能未知的GH/IGF-1轴抑制成分之间，存在着复杂的相互作用，以调节体细胞生长和葡萄糖/胰岛素稳态。
