Hampton R F, Jimenez-Gonzalez M, Kang R, Alvarsson A, Espinoza D, Carty J R E, Seibold F, Lambertini L, Alexeyev L, Li R, Devarakonda K, Lu G, Agyapong B, Choudhury J, Alon M, Scott D, Stewart A, Garcia-Ocana A, Stanley S A
Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA 91010, USA.
bioRxiv. 2025 Jul 5:2025.07.01.662442. doi: 10.1101/2025.07.01.662442.
Nutrient excess results in short- and long-term adaptations in the structure and function of metabolic organs, such as pancreatic islets. Pancreatic innervation contributes to islet architecture and function in many species, including humans, but little is known about its adaptation to over-nutrition. Here, we use 3D imaging to show that short-term high fat diet rapidly remodels islet sympathetic innervation while long-term high fat diet results in islet-specific cholinergic neuropathy. Using highly targeted, organ- and circuit-specific approaches, we demonstrate that remodeling of pancreatic innervation contributes to impaired glycemic control with short- and long-term nutrient excess. Counteracting the nutrient-induced changes in sympathetic and parasympathetic inputs to the pancreas using neuromodulation and repurposed FDA-approved approaches, we can significantly improve glycemic control even with long-term high fat diet. Finally, we identify islet Schwann cells as a source of the neurotrophic factor, S100b, contributing to rapid sympathetic hyperinnervation with short-term overnutrition. Our findings reveal novel adaptations in islet innervation contributing to nutrition-mediated metabolic dysfunction that can be ameliorated by targeting pancreatic neural circuits.
营养过剩会导致代谢器官（如胰岛）的结构和功能在短期和长期内发生适应性变化。胰腺神经支配在包括人类在内的许多物种中对胰岛结构和功能都有贡献，但人们对其在营养过剩情况下的适应性了解甚少。在此，我们利用三维成像技术表明，短期高脂饮食会迅速重塑胰岛交感神经支配，而长期高脂饮食则会导致胰岛特异性胆碱能神经病变。通过使用高度靶向、针对器官和神经回路的方法，我们证明胰腺神经支配的重塑会导致短期和长期营养过剩时血糖控制受损。利用神经调节和重新利用美国食品药品监督管理局（FDA）批准的方法来抵消营养诱导的胰腺交感和副交感神经输入变化，即使长期高脂饮食，我们也能显著改善血糖控制。最后，我们确定胰岛雪旺细胞是神经营养因子S100b的来源，它有助于短期营养过剩时交感神经的快速过度支配。我们的研究结果揭示了胰岛神经支配的新适应性变化，这些变化导致了营养介导的代谢功能障碍，通过靶向胰腺神经回路可以改善这种障碍。
