Introduction and Objective: Ghrelin regulates food intake, exercise endurance, and blood glucose; its plasma levels are increased by fasting and exercise. During fasting, the SNS stimulates ghrelin secretion via norepinephrine release onto ghrelin cells. A role for the SNS in mediating ghrelin secretion during exercise is unknown. Here, we sought to characterize the dynamic nature of ghrelin cell innervation by the SNS, the chemical identity of these SNS neurons, and the requirement of the SNS for fasting- and exercise-induced ghrelin secretion. Methods: SNS subtypes in the celiac ganglion (CG-SMG) were identified by snRNA seq. CNS projections to gastric ghrelin cells were mapped with Cre-dependent PRV-2017-EGFP tracing in Ghrelin-Cre mice. The anatomical organization of NPY axonal terminals in relation to ghrelin cells was determined by histochemistry. NPY-induced ghrelin secretion was determined in 1° gastric cell cultures. The impact of CG-SMG NPY neuronal activation on ghrelin secretion and various physiological parameters was determined with chemogenetics. Results: CG-SMG snRNA seq identified 4 SNS neuron subtypes including NPY+ neurons. A 24h fast increased NPY+ neuron contacts with ghrelin cells by 226%; this reversed by 16h of refeeding. NPY directly stimulated ghrelin secretion. Cre-dependent PRV-2017-EGFP traveled retrogradely from gastric ghrelin cells of Ghrelin-Cre mice to several brainstem and hypothalamic nuclei via the CG-SMG (90% were NPY+). Chemogenetic inhibition of CG-SMG NPY neurons reduced exercise and fasting increases in plasma ghrelin, led to greater blood glucose drops after a 24h fast (by 65%) and reduced post-HIIE food intake (by 45%) and exercise endurance (by 27%) compared to controls. These effects were rescued by ghrelin delivery. Conclusion: CG-SMG NPY neurons mediate SNS-driven ghrelin release during exercise and fasting, coordinating various gut-brain metabolic responses including changes to blood glucose, food intake, and exercise endurance. Disclosure O. Singh: None. S. Sheybani Deloui: None. S. Varshney: None. D. Gupta: None. K. Shankar: None. S. Kulkarni: None. M. Lyu: None. C. Lawrence: None. I.B. Hogue: None. S. Osborne-Lawrence: None. J.M. Zigman: Stock/Shareholder; Current; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. Funding American Diabetes Association (1-25-PDF-88), National Institutes of Health (R01DK142092-01A1); Sprouts Grant Program of the Peter O’Donnell Jr. Brain Institute at UT Southwestern Medical Center
Singh et al. (Fri,) studied this question.