Assessing the Role of Gastrointestinal Mechanosensation in the Regulation of Feeding Behavior and Glucose Homeostasis

About This Grant

PROJECT SUMMARY Obesity has risen drastically in recent decades within the United States, underscoring a critical need for more effective therapies. Despite the significant progress that has been made within the obesity research field, effective therapies for obesity are still lacking. This demonstrates the need for interventional strategies that effectively reduce body weight and maintain weight loss. Vagal afferents within the nodose ganglia (NG) that terminate in the gut (and other peripheral organs), sense postprandial signals and then relay that information to the neurons in the nucleus of the solitary tract (NTS) of the brain, a region critical for integrating peripheral signals and initiating changes in feeding behavior and glucose homeostasis. It is appreciated that disruptions in gut-brain communications like vagal afferent signaling, contribute to the pathophysiology of obesity. Vagal afferent neurons that express oxytocin receptor (OxtR) are primarily responsible for sensing stretch in the intestine and have been shown to regulate energy and glucose homeostasis. Specifically, my preliminary data demonstrates that intestinal stretch reduces food intake and that this effect is dependent on vagal OxtR signaling in female but not male mice. Intestinal stretch also increases oral glucose tolerance in male and female mice. We have also shown that diet induced obese mice of both sexes lack intestinal stretch-induced reductions in food intake and improvements in oral glucose tolerance. Lastly, intestinal stretch significantly reduces glucose levels via increased insulin secretion independent of vagal OxtR in both male and female mice. Our overarching hypothesis is that dysfunctional intestinal mechanosensation impairs satiety and glucose homeostasis in a sex-specific manner. This hypothesis will be tested using the following aims: Aim 1) To define role of vagal OxtR neurons and their central targets in regulating energy homeostasis in obesity and Aim 2) To elucidate vagal and endocrine mechanisms by which intestinal stretch regulates glucose homeostasis. Through the K01 training plan, I will master chemogenetics, single-cell transcriptomics, microsurgeries, and metabolic phenotyping, positioning me to establish an independent program dedicated to gut-brain regulation of energy and glucose balance. By clarifying how intestinal mechanosensation governs feeding and glycemic control, and how these pathways fail in obesity, this project will lay the groundwork for precision gut-targeted interventions that can sustain weight loss metabolic health.