Dissecting the gut-hypothalamus axis for fructose sensing

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

PROJECT SUMMARY Highly processed foods have become increasingly prevalent in our diets over the past several decades. These foods often contain high levels of high fructose corn syrup (HFCS), and excess intake of HFCS is associated with obesity and a host of associated metabolic diseases, such as type II diabetes and cardiovascular disease. However, the gut-brain mechanisms through which fructose is sensed, and how it influences homeostatic feeding circuits in the brain, are largely unknown. My preliminary data suggest that fructose engages the vagus nerve to inhibit activity in hunger-promoting agouti-related protein (AgRP)-expressing neurons in the brain. Building on this finding, this proposal will test the hypothesis that Y2-expressing vagal afferents sense fructose in the gut and are sufficient and necessary for gut fructose-induced inhibition of AgRP neuron activity. Aim 1 will use single- cell resolution two-photon calcium imaging to determine the real-time activity dynamics of fructose-activated vagal afferents. In a complementary experiment, we will combine retrograde tracing to label gut-innervating vagal afferents, with activity-dependent gene labeling via in situ hybridization in mice, to determine the molecular identity of gut-innervating fructose-activated vagal afferents. Aim 2 will leverage an activity-dependent technique to gain genetic access to fructose-responsive neurons to determine their role in modulating AgRP neuron activity Through these experiments, we expect to reveal the gut-hypothalamic nutrient sensing pathway for fructose. These results will not only provide new insight for the field of gut-brain signaling, but will also have clinical applications by uncovering new potential drug targets for obesity treatment. My Sponsor, Dr. Amber Alhadeff, is an expert in the gut-to-AgRP neural pathways involved in nutrient sensing, and my Co-sponsor, Dr. Guillaume de Lartigue, has extensive experience with anatomical tracing and two-photon microscopy of vagal afferents. My prior research experience, combined with the expertise of both Sponsors, make me uniquely positioned to successfully complete all proposed experiments during my graduate training. Therefore, funding of this NRSA proposal to support my dissertation studies will set me on the trajectory toward my ultimate goal of becoming an independent investigator that explores gut-brain circuits that regulate feeding.