Search

The growth hormone receptor (GHR) is expressed in brain regions that are known to participate in the regulation of energy homeostasis and glucose metabolism. We generated a novel transgenic mouse line (GHRcre) to characterize GHR-expressing neurons specifically in the arcuate nucleus of the hypothalamus (ARC). Here, we demonstrate that ARCGHR+ neurons are co-localized with agouti-related peptide (AgRP), growth hormone releasing hormone (GHRH), and somatostatin neurons, which are activated by GH stimulation. Using the designer receptors exclusively activated by designer drugs (DREADD) technique to control the ARCGHR+ neuronal activity, we demonstrate that the activation of ARCGHR+ neurons elevates a respiratory exchange ratio (RER) under both fed and fasted conditions. However, while the activation of ARCGHR+ promotes feeding, under fasting conditions, the activation of ARCGHR+ neurons promotes glucose over fat utilization in the body. This effect was accompanied by significant improvements in glucose tolerance, and was specific to GHR+ versus GHRH+ neurons. The activation of ARCGHR+ neurons increased glucose turnover and whole-body glycolysis, as revealed by hyperinsulinemic-euglycemic clamp studies. Remarkably, the increased insulin sensitivity upon the activation of ARCGHR+ neurons was tissue-specific, as the insulin-stimulated glucose uptake was specifically elevated in the skeletal muscle, in parallel with the increased expression of muscle glycolytic genes. Overall, our results identify the GHR-expressing neuronal population in the ARC as a major regulator of glycolysis and muscle insulin sensitivity in vivo.

We are facing a worldwide public health emergency due to the increasing epidemic of diabetes. In the central nervous system, the hypothalamus is the primary site of integration of the neuroendocrine and autonomic responses which maintain glucose and energy homeostasis. Main physiological effects of growth hormone (GH) in adult brain - is the inhibition of its own secretion, especially critical under fasting states. While the importance of hypothalamic GH receptor (GHR) in GH feedback inhibition is well established, the direct involvement of neuronal GHR signals in the regulation of whole-body homeostasis has not been studied. Previously, we have identified a unique population of hypothalamic leptin receptor (LepRb)-GHR expressing neurons that regulate hepatic glucose production, suggesting a crucial role for these neurons in GHR-neurocircuitry. To characterize hypothalamic GHR-expressing neurons, we have developed GHRcre mice using CRISPR/Cas9 technology. Approximately 60% of GHR+ neurons in the arcuate nucleus (ARC) co-localize with AgRP-expressing neurons and about 25% with GHRH neurons, basically representing most of ARCGHR neurons. By manipulating neuronal activity of neurochemically-defined GHR neurons, we demonstrate that ARCGHR neurons represent distinct neuronal population in glycemic control. Despite similarity in responses in both sexes, only female mice selectively lacking GHR in AgRP neurons showed impaired energy homeostasis and heat production, accompanied by alterations in metabolic adaptation to fasting. Fasting increased the abundance of sirtuin 1 (SIRT1) within ARCGHR+ neurons, while this pattern was diminished in the fasted AgRPEYFP∆GHR female mice. Our data suggests a role of SIRT1 within somatotropic signaling in the AgRPGHR+ neurons in response to alterations in nutritional status and demonstrates the role of AgRP-GHR neurons in assisting the organism in recruiting its resources for survival purposes. Disclosure L.K. Debarba: None. I.T. Ayyar: None. M.C. Koch: None. G. Cady: None. M. Sadagurski: None. Funding American Diabetes Association (1-18-JDF-063 to M.S.)