The importance of growth hormone's action on NPY/AgRP neurons

Abstract

Neurons that co-express the neuropeptide Y (NPY) and agouti-related protein (AgRP) are located in the arcuate nucleus (ARC) of the hypothalamus. These neurons, via their neurotransmitters, are the more potent appetite stimulants. Growth hormone (GH) acts on peripheral tissues and is directly related to various functions of the organism such as metabolism, somatic growth and cellular processes. GH releasing hormone, somatostatin, in addition to free fatty acids, leptin, ghrelin and neuropeptide Y, are important factors that control the pituitary secretion of GH. Also the nutritional status, the intense physical activity, the stress, the hypoglycemia and fasting are potent regulators of its release. There is evidence that GH may have effects on the Central Nervous System (CNS), mainly on the regulation of appetite, cognition, memory, sleep, neural protection and well-being. Our research group has recently conducted a detailed mapping study to describe the distribution of GH responsive cells in the mouse CNS. The results of this study indicated large presence of GH-responsive cells in several brain areas, including those controlling the energetic and glycemic metabolism. The great presence of GH responsive cells in ARC does not guarantee the expression of the GH receptor (GHR) in all neuronal clusters forming this nucleus. However, some studies indicated that 95% of the NPY / AgRP neurons of the ARH show GHR expression. In order to be able to study the action of GH specifically on NPY / AgRP neurons of the ARC, we will use the Cre-LoxP system that allows tissue-specific gene manipulation. Thus, we will produce mice that present GHR inactivation exclusively in ARC NPY / AgRP neurons. These animals will be studied to assess possible changes in control of energy balance, glycemic homeostasis and during situations which increase GH circulating levels, in order to investigate the importance of GH signaling in ARC NPY / AgRP neurons. Ours results may reveal for the first time a possible effect of the GH on the CNS to control several metabolic aspects. These effects could be mediated by ARC NPY / AgRP neurons, specialized in integrating information from different hormones to control metabolism. (AU)