Nutrient regulation of the EEC-vagal network

Ohio State University, Columbus OH

Investigators

Abstract

Project Summary The increased high-sugar and high-fat diet consumption directly contributes to the prevalence of obesity and metabolic disorders. The enteroendocrine cells (EECs) are critical chemosensory cells in the intestinal epithelium. Following food ingestion, the nutrients in the intestinal lumen are sensed by a subset of EECs. Recent research demonstrated that the EECs that express Cholecystokinin (CCK) possess basal membrane processes called neuropod to form synaptic connections with the vagal sensory nerve fiber. Through the CCK+EECs-vagal synaptic connection, the nutrient information in the intestinal lumen can be sensed and transmitted to the brain. The CCK+EEC-vagal circuitry plays important roles in regulating food preference and feeding behavior. However, the molecular mechanisms and the environmental factors that regulate the EEC-vagal synaptic connections remain entirely unknown. Moreover, our general understanding of the signaling molecules that drive the vagal innervation in the intestine and the mechanisms that regulate the intestinal vagal network remains extremely limited. As a result, our ability to manipulate intestinal vagal signaling and target gut-brain nutrient sensing to treat diseases associated with feeding dysfunction and metabolic disorders is handicapped. The proposed study will use novel genetic tools in zebrafish models and in vivo imaging to directly visualize the dynamic EEC-vagal synaptic communication in live animals. Our preliminary data demonstrate that EECs are important for remodeling the intestinal vagal network and CCK+EECs express Brain-derived neurotrophic factor (Bdnf). This proposal will test the central hypothesis that feeding and nutrients dynamically regulate CCK+EECs Bdnf signaling to remodel CCK+EEC-vagal synaptic connections and the intestinal vagal network. The first aim will use genetic tools and CRISPR screening to determine the environmental factors and molecular mechanisms that regulate Bdnf expression in CCK+EECs. The second aim will use a novel genetic approach to directly visualize in vivo EEC-vagal synaptic connections to determine the role of Bdnf signaling in CCK+EECs in regulating the EEC-vagal synaptic connections and the intestinal vagal network. Accomplishing this proposal is expected to reveal the first molecular mechanism and cellular signaling that drive the formation of the EEC-vagal synaptic connection. It will reveal novel mechanisms that modulate the intestinal vagal network, enhance EEC-vagal signaling transmission, and promote gut- brain nutrient sensing. Selectively manipulating the EEC Bdnf signaling will offer new opportunities to treat diseases that are associated with vagal disorders and gut-brain nutrient sensing dysfunction.