The neurotransmitter for calorie

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PROJECT SUMMARY/ABSTRACT The main motivation to feed is to obtain energy from nutrients. Thus, the maintenance of body weight depends upon circuits which recognize the value of nutrients to guide food intake. The sensory cell of the gut, the enteroendocrine cell, communicates to the brain via hormones to regulate food intake over tens of minutes to hours. In 2018, we discovered that a subset of enteroendocrine cells make synaptic contact with the vagus nerve. We named these synpatically connected cells neuropod cells. Neuropod cells communicate the presence of carbohydrate in the duodenum to the vagus nerve within 60 milliseconds using glutamate neurotransmission. However, the information encoded by glutamate is unknown. This application tests the hypothesis that glutamate neurotransmission from gut to the vagus nerve encodes the energy value of nutrients. This hypothesis will be tested in two specific aims. Specific Aim 1 will use organoid (“mini gut”) and enteroendocrine cell culture from mice to examine glutamate release in response to nutrient stimulation. We hypothesize that glutamate released from enteroendocrine cells encodes nutrient value, based upon the unit energy provided by the nutrient (i.e, kilocalorie) rather than the macronutrient content. Therefore, we predict that glutamate will be released in a kilocalorie-dependent, rather than a macronutrient-dependent manner. Specific Aim 2 will use in vivo multiphoton calcium imaging of the vagal nodose ganglia in transgenic mice which express the calcium indicator GCaMP6s in vagal nodose neurons. Single cell resolution of vagal neuron activity will be recorded in response to nutrient delivery to the duodenum. If neuropod cell glutamate release conveys information specific about energy value, rather than macronutrient content, then separate macronutrients of equal caloric value should stimulate overlapping vagal neuron populations. By defining the functional relevance for rapid gut-to-vagus glutamatergic signaling, these studies will provide new fundamental biology of gut-brain communication. This work will contribute new possible avenues of pharmacotherapies for the treatment of nutrient-intake related disease, namely obesity.