New Tools for Investigating Enteric Neural Circuit Dysfunction in Obesity and Type 2 Diabetes
Abstract
Obesity and its complications, particularly Type 2 diabetes mellitus (T2DM), have reached epidemic proportions in the military and civilian populations. An estimated 10% of the population worldwide either already has or will develop T2DM over the course of their lifetimes. The prevalence, complications, and enormous healthcare costs associated with these disorders are on the rise despite decades of research, suggesting that new approaches for prevention and treatment are desperately needed. Weight loss surgeries such as gastric bypass are by far the most effective therapies for obesity and lead to dramatic short- and long-term improvements in diabetes among obese patients. But surgery is invasive, costly, and inherently risky; identifying non-surgical alternatives that can produce similar improvements would be a major step forward in treatment. The rapid improvement in T2DM following bariatric surgery occurs independently of weight loss and has been linked to changes in enteroendocrine cells (EECs). EECs are a set of hormone-producing cells scattered throughout the intestine that detect ingested nutrients as they pass through the gut and release signaling molecules in response. These cells are on the front lines of identifying what nutrients are in the food we eat and organizing the body’s response. For example, signals released by EECs upon detecting a meal stimulate the pancreas to secrete more of the hormone insulin, preventing blood sugar levels from rising too high. There is growing evidence that EEC signaling to adjacent nerves is an important means by which the body uses nutrient information to coordinate behavioral responses such as how much we eat, how fast ingested food moves through the gut, and how the body stores energy, but relatively little is known about this signaling. A better understanding of EEC-nerve signaling and why this communication is important could uncover new therapeutic targets for preventing and treating diabetes at the level of the gut, without invasive surgeries. The nerves that most commonly interact with EECs belong to a unique population of sensory nerve cells located in the walls of the gastrointestinal tract, called intrinsic primary afferent neurons (IPANs). Until now, major barriers have prevented precise study of how EECs signal to these nerves and how this signaling affects metabolism and blood sugar regulation. We have developed an innovative genetic approach to overcome these barriers that enables the study of EEC-nerve cell communication in mice. We will use this approach to determine how EECs and IPANs wire together, and how disrupting signaling between these two cell types alters appetite, body weight, and blood glucose regulation before and after meals. These experiments will lead to a new understanding of the role of gut nerves in T2DM and potentially reveal novel therapeutic targets for obesity and its complications. These studies will also serve as an important proof of principle for our novel genetic approach, which could be widely applied to understanding the role of the “second brain” in the gut in a variety of digestive and neurological disorders.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810639
Entities
People
- Meenakshi Rao
Organizations
- United States Army