Background: Pancreatic islets are richly innervated. Use of 2D immunohistochemistry and extreme models of obesity and diabetes have limited our understanding of pancreatic nerve anatomy. Additionally, our knowledge of the direct roles of pancreatic nerves in regulating pancreatic function is incomplete. Determining how high-fat diet (HFD) impacts pancreatic nerve structure and function will provide novel insights into the mechanisms and pathophysiology of obesity and type 2 Diabetes.
Aim: To create a comprehensive atlas of pancreatic sympathetic and parasympathetic fibers throughout the pancreas and the time course of HFD-induced structural changes and to determine the direct physiological roles of pancreatic efferent nerves on islet hormone secretion. Hypothesis: HFD increases islet sympathetic density and activity, while decreasing islet parasympathetic density and activity, leading to insufficient plasma insulin to maintain normoglycemia.
Methods: C57BL/6 mice were randomized to HFD or low-fat diet (LFD) groups. Weekly metabolic phenotyping was determined. Pancreata were cleared and immunolabeled according to iDISCO+, imaged by lightsheet microscopy, and analyzed using Imaris software. To test the roles of pancreatic parasympathetic nerves on islet hormone release, cre-dependent hM3D (Gq) -mCherry or mCherry viral constructs were injected into the pancreatic duct of ChAT-IRES-cre mice. ChAT-IRES-cre mice were fed LFD or HFD and the effects of neuromodulation were assessed.
Results: HFD significantly impairs glucose tolerance and insulin sensitivity and rapidly remodels islet sympathetic and parasympathetic innervation. Targeted activation of pancreatic parasympathetic efferent nerves significantly improves glucose tolerance after HFD consumption.
Conclusion: HFD rapidly remodels pancreatic innervation which may contribute to insufficient insulin release to maintain normoglycemia. Targeted activation of pancreatic parasympathetic nerves improves glycemic control.
R.F.Hampton: None. A.Alvarsson: None. M.Jimenez gonzalez: None. R.Y.Li: None. K.Devarakonda: None. S.Stanley: None.
NIH F31 Predoctoral Fellowship (1F31DK129016-01A1)