Structure and Function of Pancreatic Neural Circuitry in Obesity and Diabetes

INTRODUCTION: Pancreatic islets are richly innervated by autonomic nerves which contribute to physiological regulation of islet hormone release and blood glucose. Published studies suggest obesity disrupts pancreatic innervation and may contribute to metabolic dysfunction. However, these studies largely rely on 2D imaging of islets and experiments aimed at assessing the function of pancreatic nerves have not been organ specific. Determining how high-fat diet (HFD) impacts pancreatic nerve structure and function using 3D imaging and organ-specific neuromodulation may provide new insights into the pathophysiology of diabetes and identify novel therapeutic approaches to treat diabetes. METHODS: To test the hypothesis that HFD causes structural changes in pancreatic innervation, C57Bl6 mice were randomized to 1, 4 and 12 week high-fat (HFD) or low-fat diet (LFD) groups. Metabolic phenotyping was determined. Pancreata were cleared and immunolabeled using iDISCO+, imaged by lightsheet (4X) and confocal (10X) microscopy and images were analyzed using Imaris software. To test the effects of HFD on pancreatic nerve function, we used AAV8 delivery of cre-dependent neuromodulatory constructs to activate or silence pancreatic parasympathetic or sympathetic nerves. To modulate pancreatic parasympathetic nerves, we delivered cre-dependent hM3D(Gq) for activation, cre-dependent diphtheria toxin A subunit for silencing, or mCherry (control) into the pancreas of Chat-cre mice. To modulate pancreatic sympathetic nerves, we used pancreatic injection of retrograde AAV delivering cre and celiac injection of cre-dependent hM3Gq (activation), hM4Gi (silencing) or mCherry (control). Mice were fed LFD or HFD for up to 12 weeks and the effects of neuromodulation on glucose metabolism were examined. RESULTS: HFD significantly impaired glucose tolerance, insulin sensitivity and altered plasma insulin and glucagon after 1, 4 and 12 weeks of HFD consumption. HFD consumption significantly altered pancreatic neural structure. Within islets, 1 week of HFD significantly increased sympathetic neural volume. With prolonged HFD, there was significant loss of islet parasympathetic innervation. Reproducing loss of islet parasympathetic innervation impaired glucose tolerance but sympathetic activation did not alter glucose metabolism. Targeted silencing of pancreatic sympathetic innervation or activation of pancreatic parasympathetic innervation significantly improved glucose tolerance in hyperglycemic mice fed HFD. CONCLUSION: Short term HFD causes early rapid changes to islet sympathetic nerves while long term HFD consumption results in loss of pancreatic parasympathetic innervation of the islet. The effects of HFD consumption are improved by inhibiting pancreas-projecting sympathetic fibers or through activation of pancreatic parasympathetic nerves. These studies suggest modulating pancreatic innervation may improve glucose control in obesity. NIH F31 Predoctoral Fellowship (1F31DK129016-01A1, R.H.) ISMMS MSTP T32 (GM007280) NIH (R01NS097184, OT2OD024912, S.S.) American Diabetes Association (ADA #1-17-ACE-31, S.S) Department of Defense (W81XWH-20-1-0345, S.S). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.