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.