The role of growth hormone in the brain: relevance for neural functions and in disease

Abstract

GH is the most abundant factor secreted by the pituitary gland and plays an important role controlling somatic and tissue growth, as well as cell proliferation and differentiation. Despite the presence of the GH Receptor (GHR) in the brain, little is known about the effects of this hormone on the nervous system. Thus, we propose in this project that GH has a previously unrecognized role in the nervous system. Our hypothesis is that the brain mediates important aspects of the biological effects of GH, particularly regarding the metabolism. Therefore, the aim of the present project is to investigate the importance of GH signaling in the nervous system by manipulating GHR expression in specific populations of neurons. To do so, we will use mice from the Cre/loxP system that allow the inactivation of GHR or its main intracellular signaling pathway, STAT5, in neuronal populations of interest. We will produce mice with selective inactivation of GHR and/or STAT5 throughout the nervous system, in leptin receptor-expressing cells, in neurons of the ventromedial nucleus of the hypothalamus (SF1 positive cells) and in neurons expressing AgRP, orexin or tyrosine hydroxylase. These different mouse models will be studied in 14 subprojects aimed at investigating the importance of central GH signaling in multiple neurological functions, including metabolic control, cognition, wake-sleep cycle, memory/learning, behavior, emotions/motivation, as well as in neurovegetative and neuroendocrine functions. The knowledge that will be generated by the experiments proposed may change our notion about the function and mechanisms of action of one of the most important hormones. (AU)