PROJECT SUMMARY Metabolic dysregulation is a central node underlying many age-dependent diseases including diabetes, cardiovascular disease, cancer and neurodegeneration, and more generally, is thought to accelerate the aging process. Two organ systems decode sensory information to control energy metabolism throughout the body: the central nervous system, and the gut. How we regulate our metabolism and the interplay between the brain and the gut in this process are major unanswered questions in biology and medicine. The long-term goal of my laboratory is to understand mechanisms of neuroendocrine communication between the brain and the gut, and the defects in this process that lead to diseases of energy dysregulation. We use the C. elegans model for our work, a tremendously useful system to map energy balance circuits and visualize the gut-brain axis in living animals. My lab has identified a neuronal circuit in the brain that integrates sensory information from the environment, and drives systemic fat loss via a tachykinin brain-to-gut signaling pathway. In a surprising twist, we find that intestinal fat status modulates the tachykinin-secreting neurons in this circuit, suggesting that internal nutrient state information is relayed directly from the gut, back to the brain. A genetic screen for interoceptive molecules revealed two peptides: INS-7, a member of the insulin/relaxin superfamily, and NLP-7, a member of the cholecystokinin/gastrin family. Our central hypothesis is that gut-brain peptides relay internal state information from the intestine to tune neuronal responses and control the extent to which the nervous system is able to modulate whole-body metabolism and behavior. Aim 1. Decoding the effects of gut signals on sensory neurons that control body fat. We will elucidate the molecular mechanisms by which INS-7 signaling modifies sensory neuron properties to alter whole-body metabolism. Aim 2. Defining gut-to-brain signals underlying internal state-dependent food-seeking behavior. We will identify mechanisms by which NLP-7 from the gut regulates food-seeking and provide a functional map of gut-responsive interoceptive neurons. Aim 3. Deciphering mechanisms by which gut sensory and metabolic functions are coupled to enteroendocrine secretions. We have developed methodologies to visualize and quantify secreted peptides in living animals. We will harness this capability to conduct a genetic screen and define the molecular pathways by which the sensing of internal nutrient and fat status regulates the release of gut endocrine peptides. The objective of this application is to decode the molecular and endocrine mechanisms by which interoceptive information from the gut is integrated into the neuronal sensory circuits, and how it influences lipid metabolism and food-seeking behavior. In so doing, we will define the core cellular and molecular components of the gut-brain axis. Other expected outcomes are that we will provide the first sensory a...