ESPE Yearbook of Paediatric Endocrinology

Brief summary: This translational study evaluated mRNA expression of hypothalamic neuroglial markers in two transgenic mice with either enhanced or reduced consensual GH-IGF-1 signaling and in Hepatocyte-specific GH receptor (GHR) knockout male mice, with high GH circulating-levels and low IGF-1 concentrations. The study demonstrated a direct action of GH on neuroinflammation, independently of IGF-1 levels.

Although the brain is not considered a classical target tissue of GH, recent studies conducted in animal models and humans highlighted the potential role of GH in brain functions, such as spatial learning, memory and stress resilience in particular in the hippocampal region (1,2,3). However, these effects may be indirect and mediated by insulin and IGF1 [4,5]. Neuroglial cells represent the most numerous cell family in the central nervous system and contribute to brain homeostasis, supporting synaptic contacts and neuron signalling. This study aimed to determine the action of GH in the regulation of neuroglial and proinflammatory markers in the hypothalamus of male mice. GH-IGF1 deficient mice with a null mutation in the GH-releasing hormone receptor gene, showed decreased mRNA expression of Nes (Nestin), Gfap, Iba1, Adgre1 (F4/80), and Tnf (TNFα) compared to wild-type animals. Conversely, mice with transgenic overexpression of bovine GH with high serum GH and IGF-1 levels had increased hypothalamic expression of Nes, Gfap, Adgre1, Iba1, and Rax. In order to investigate the direct effect of GH on neuroglia independently from IGF-1, the authors utilized mice with knockout of hepatocyte GH receptor (GHR), having high serum GH levels, but reduced IGF-1 concentrations. Hepatic GHR-ablated mice showed increased mRNA expression of Gfap, Iba1, Tnf, and Sox10, thus indicating that GH has a direct effect on the hypothalamic expression of glial markers associated with neuroinflammation. Conversely, brain-specific GH-Receptor (GHR) knockout mice showed reduced expression of several neuroinflammatory markers. Taken together these experimental findings suggest that GH exerts a direct effect on neuroglial markers of inflammation in male mice.

References: 1. Basu A, McFarlane HG, Kopchick JJ. Spatial learning and memory in male mice with altered growth hormone action. Horm. Behav. 2017;93:18–30. https://doi.org/10.1016/j.yhbeh.2017.04.001. 2. Hascup KN, Lynn MK, Fitzgerald PJ, Randall S, Kopchick JJ, Boger HA, et al. Enhanced cognition and hypoglutamatergic signaling in a growth hormone receptor knockout mouse model of successful aging. J. Gerontol. A Biol. Sci. Med. Sci. 2017;72:329–337. https://doi.org/10.1093/gerona/glw088. 3. Vander Weele CM, Saenz C, Yao J, S.S. Correia, K.A. Goosens, Restoration of hippocampal growth hormone reverses stress-induced hippocampal impairment. Front. Behav. Neurosci. 2013;7:66. https://doi.org/10.3389/fnbeh.2013.00066. 4. De Felice FG. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J. Clin. Invest. 2013;123:531–539. https://doi.org/10.1172/JCI64595. 5. Ajo R, Cacicedo L, Navarro C, Sanchez-Franco F. Growth hormone action on proliferation and differentiation of cerebral cortical cells from fetal rat. Endocrinology, 2003;144:1086–1097. https://doi.org/10.1210/en.2002-220667.