Meeting abstracts from the 2020 International Meeting on GH/IGF: actions in the shadow of COVID19
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ABSTRACT
Meeting abstracts from the 2020 International Meeting on GH/IGF: actions in the shadow of COVID19
© Springer Science+Business Media, LLC, part of Springer Nature 2020
The central nervous system T01 Novel roles for hypothalamic growth hormone (GH) axis in metabolic regulation Juliana Bezerra Medeiros de L ima1, Lucas D ebarba1, Mari1 anna Sadagurski * 1 Wayne State University, Detroit, MI, USA In the central nervous system (CNS), growth hormone (GH) is present in regions known to participate in the regulation of feeding, energy balance, and glucose metabolism, including the hypothalamus, hippocampus, and amygdala [1–5]. The expression of GH receptor (GHR) within the CNS has been mapped by in situ hybridization and by detection of the downstream target, the phosphorylated activator of transcription (STAT) 5, revealing large numbers of GHresponsive neurons in various brain regions [2, 6, 7]. While these studies detected GHR expression within the CNS, the functional assessment of the GHR-expressing neurons in various brain regions was lacking. To characterize the role of GHR-expressing neurons, we have developed a novel GHR-driven cre mouse ( GHRcre) using the CRISPR/Cas9 gene-editing technology. G HRcre mouse line was validated by a cre-dependent Rosa26-tdTomato reporter mouse. The expression pattern of tdTomato reporter revealed the presence of GHRcre-expressing neurons in the several areas of the hypothalamus, including the midbrain and hindbrain (Figure T01). We have recently shown that neuronal-specific deletion of GHR in leptin receptor (LepRb)-expressing neurons in the hypothalamus impaired hepatic glucose production and systemic lipid metabolism. LepRb neurons co-express GHR in the ARC, DMH and LHA, suggesting
the role of GHR in these neurons as an integrating locus of regulation of glucose metabolism [8]. To this end, we focused on neurons of the hypothalamic arcuate nucleus (ARC) where GHR was shown to elicit a negative feedback loop that regulates GH production. We found that ARC GHR+ neurons are co-localized with agouti-related peptide (AgRP), GH-releasing hormone (GHRH), and somatostatin neurons, which were activated by GH stimulation. Utilizing these mice, we studied the functional roles of GHR neurons in the ARC in the regulation of systemic glucose metabolism and energy homeostasis. Using designer receptors exclusively activated by designer drugs (DREADDs) to control GHRARC neuronal activity, we revealed that activation of G HRARC neurons acutely increased systemic glucose sensitivity, energy expenditure, and heat production. To distinguish between different neuronal subsets within the GH axis in the ARH, we crossed GHRH-specific Cre driver line to DREADD-hM3Dq transgenic mice to selectively activate all GHRH neurons. In contrast to GHRARC activation, selective activation of all GHRH neurons, had no effect on glucose tolerance, food intake or body weight. The majority of GHRARC neurons express Sirtuin 1 (SIRT1) and respond to fasting by upregulating the SIRT1 expression.
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