SUN-683 - Metabolic Responses to Exercise Depend on Sympathetic Innervation of Gastric Ghrelin Cells

Objective
The stomach hormone ghrelin regulates food intake – including eating after exercise, exercise endurance, and blood glucose, with circulating levels increased by fasting and exercise. During fasting, the sympathetic nervous system (SNS) stimulates ghrelin release from specialized enteroendocrine ghrelin cells in the gastric mucosa through norepinephrine-dependent activation of ghrelin cell-expressed β1-adrenergic receptors. A role for the SNS in mediating ghrelin release during exercise is unknown. Here, we sought to characterize the dynamic nature of ghrelin cell innervation by the SNS, the chemical identity of the ghrelin cell-projecting SNS neurons, and the requirement of the SNS for caloric restriction-induced and exercise-induced ghrelin release.

Methods
Distinct sympathetic neuronal subtypes within the celiac ganglion-superior mesenteric ganglion (CG-SMG) were identified by snRNAseq. 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 in ad lib-fed, 24h fasted, and 16h refed mice and activation of these neurons by high-intensity interval exercise (HIIE) were determined by immunohistochemistry. NPY-induced ghrelin secretion was determined in 1 gastric mucosal cell cultures. The impact of CG-SMG NPY neuronal activation on eating after HIIE, exercise endurance, fasting blood glucose, and circulating ghrelin was determined with chemogenetics.

Results
CG–SMG snRNA-seq identified 4 SNS neuronal subtypes: Cntn5⁺, Nrg1⁺, NPY⁺TH/Dbh⁺, and NPY-only neurons. A 24h fast raised the number of NPY+ axonal terminal contacts with ghrelin cells by 226%; this reversed within 16h of refeeding. Ghrelin release from cultured gastric mucosal cells increased by 22% in response to 1 µM NPY. 28% of CG-SMG NPY neurons were activated by HIIE. Cre-dependent PRV-2017-EGFP traveled retrogradely from gastric ghrelin cells of Ghrelin-Cre mice to several brainstem (AP, NTS, DMNV) and hypothalamic (PVN, AH, LH) nuclei, via the CG-SMG and IML. 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.

Conclusions
CG-SMG NPY neurons mediate SNS-driven ghrelin release during exercise and caloric restriction, coordinating gut-brain metabolic responses.

Disclosure: JMZ owns stock in Eli Lilly and Novo Nordisk.

Funding. This work was supported by NIH R01DK142092-01A1; an American Diabetes Association (ADA) Postdoctoral Fellowship (1-25-PDF-88); and the Sprouts Grant Program of the Peter O’Donnell Jr. Brain Institute at UT Southwestern Medical Center.

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