Pancreatic Neural Circuitry in Obesity and Diabetes

项目总结/文摘:

Project Summary/Abstract: Obesity is extremely prevalent in the United States, and linear trend forecasts suggest that more than 50% of the population will suffer from obesity by 20301. Obesity increases the risks for developing chronic health conditions, such as Type 2 diabetes (T2D). The biology of obesity and diabetes, as well as the mechanisms linking them, are complex and poorly understood, which has impacted our abilities to effectively treat T2D. Only one third of people living with diabetes achieve adequate glycemic control, suggesting a need for more effective therapies1,35. Further investigation into the impact of obesity on the endocrine pancreas is imperative to understanding the etiology and pathogenesis of T2D, which may provide a foundation for future mechanistic and pharmacological studies aimed at preventing and treating T2D. The pancreas, and especially islets, are richly innervated and nerve density is abnormal in diabetes and obesity. However, since previously published studies predominantly use 2D imaging and extreme models of obesity, we do not have detailed mapping of pancreatic innervation in a clinically relevant model. Our approach will overcome these limitations by determining the effect of a HFD on structural and regional changes in pancreas innervation in cleared tissue. Our preliminary studies indicate that a 60% HFD increases sympathetic innervation within mouse islets, and may also decrease parasympathetic innervation. Since structure and function are related, determining how a HFD impacts nerve structure will provide novel insight into the effect of a HFD on islet function. The importance of neural signals in controlling pancreatic hormone release has been shown in many species, including humans. However, many studies use nerve stimulation strategies, which impact multiple organs, and sensory and motor pathways, so it is unknown if neural signaling within the pancreas impacts islet hormone secretion. Our preliminary studies show that the specific activation of pancreatic parasympathetic neurons improves glucose stimulated insulin secretion, and significantly reduces plasma glucose levels during a GTT after 3 and 7 days of HFD feeding (45%). Our preliminary studies strongly support the hypothesis that a HFD increases islet sympathetic activity and decreases islet parasympathetic activity, leading to insufficient insulin to maintain normal plasma glucose. This hypothesis will be tested in the following aims: Aim 1- to use iDisco+, a whole mount immunolabeling technique, in conjunction with high resolution imaging, to determine the effects of a HFD on the 3D structure of islet sympathetic and parasympathetic nerves. Aim 2- To utilize DREADD technology to regulate activity in pancreatic nerves and determine the effect of a HFD on parasympathetic and sympathetic control of islet hormone secretion. The findings of this proposal will determine the structure and function of pancreatic neural populations in normal physiology and after high fat diet feeding, ultimately providing new insight into the mechanisms and pathophysiology of T2D, which can promote the development of more effective therapies aimed at the prevention and treatment of T2D.