Regulation of ghrelin secretion by the sympathetic nervous system (SNS) - PROJECT SUMMARY This proposal focuses on actions of the sympathetic nervous system (SNS) to control ghrelin secretion. Ghrelin is a hormone produced primarily by enteroendocrine “ghrelin cells” in the lining of the stomach. Understanding the mechanisms that control ghrelin secretion is highly significant given ghrelin’s key roles in regulating metabolic processes, including eating, physical activity, and blood glucose. Ghrelin engages hedonic eating behaviors, ghrelin action is required for the usual rebound food intake following a fast, and ghrelin increases exercise endurance and regulates food intake after exercise. Also, ghrelin prevents life- threatening hypoglycemia in mice subjected to chronic caloric restriction. Previous work has identified the SNS as a primary driver of increased ghrelin secretion in response to fasting. We showed that norepinephrine (NE), which is released from SNS nerve terminals originating in the celiac ganglion, activates β1-ARs (adrenergic receptors) on ghrelin cells to stimulate ghrelin secretion during a 24h fast and a chronic caloric restriction protocol. Despite this, specific aspects of how the SNS regulates ghrelin secretion remain unknown. The overall goal of this proposal is to close these gaps in knowledge and provide a comprehensive understanding of SNS-driven ghrelin secretion. In Aim 1, we will determine how fasting and exercise change SNS innervation of ghrelin cells, using a combination of histochemistry, neuroanatomical tract tracing, and transcriptomics. In Aim 2, we will identify the specific SNS neuronal populations responsible for ghrelin secretion during fasting and exercise. This will be achieved by determining the requirement of ghrelin cell β1-AR and NPY Receptor subtype 5 (NPY5R) for fasting-induced and exercise-induced stimulation of ghrelin secretion and for the ensuing effects of this secreted ghrelin on rebound food intake after fasting, food intake after exercise, and exercise endurance. Also, we will use chemogenetics to manipulate (inhibit and separately, stimulate) activity of the different celiac ganglion neuronal populations that innervate ghrelin cells. In Aim 3, we will determine if the SNS works coordinately with insulin to regulate ghrelin secretion. This will be achieved by disrupting the presumed usual balance between SNS and insulin required for appropriate ghrelin secretion. To do this, we will generate mice with ghrelin cell-specific deletion of either insulin receptors, β1-ARs, or both. Using both in vivo models and primary gastric mucosal cell cultures from those mice, we will evaluate ghrelin secretion in response to NE and insulin and under conditions that include a fast-refeed model and diet-induced obesity. Overall, our studies will identify the SNS subtypes that innervate ghrelin cells, those synaptic and transcriptional changes within ghrelin cell-innervating SNS neurons and ghrelin cells occurring as a result of caloric restriction and exercise, the requirement of ghrelin cell β1-ARs and NPY5Rs for fasting-induced and exercise-induced ghrelin secretion, food intake, and exercise endurance, and how the SNS and insulin coordinately regulate ghrelin secretion during fasting, postprandially, and in diet-induced obesity.
