Insulin and sweet taste: mechanisms of metabolic-gustatory integration - PROJECT SUMMARY/ABSTRACT Feeding decisions are strongly influenced by the sensory attributes of food, such as taste (gustation). Critically, the nervous system integrates this external food sensing with internal nutrient sensing to coordinate appropriate feeding behaviors. Disruptions in either of these processes can lead to desynchrony, altered dietary choices, and an increased risk of chronic diseases. In turn, certain diseases, infections, or medications can alter the sense of taste to promote malnutrition and compound negative health outcomes. The overarching goal of this proposal is to expand our knowledge in the area of sensory nutrition by describing novel connections between the major metabolic regulator insulin and sweet taste sensitivity that ultimately impact sugar intake. This research combines innovative in vivo and in silico experiments in the fruit fly, Drosophila melanogaster, to overcome technical limitations in rodent models and identify conserved principles of sensory- metabolic integration. Across species, sweet taste acts as an appetitive feeding signal to promote the consumption of energy, but a less understood consequence of sweet taste is triggering the cephalic phase insulin response (CPIR). This anticipatory endocrine response prepares the body for nutrient uptake and utilization, but how exactly sweet taste cells communicate with insulin-producing cells to mediate this rapid response remains unknown. This project uses a multidisciplinary approach to determine the degree to which sweet taste cell activity is necessary and sufficient to induce a CPIR through neural circuits (Aim 1). When insulin increases in circulation, whether due to the CPIR or after food intake, this hormone plays a critical role in promoting satiety. It is currently unknown if insulin may directly impact taste sensitivity to encourage feeding cessation, but the expression of insulin receptors in sweet taste cells of both mammals and Drosophila suggests this is a possibility. To address this research gap, proposed experiments will express inactive or overactive insulin receptors, specifically in sweet taste cells, and quantify changes to sweet taste sensitivity at a cellular and behavioral level (Aim 2). This project uses a combination of cutting-edge neuroscience techniques, including optogenetics, chemogenetics, in vivo calcium imaging, connectomics, computational modeling, and quantitative feeding assays, to provide a comprehensive description of the reciprocal connections between insulin and sweet taste at a molecular, cellular, circuit, and behavioral level. The results will reveal how taste inputs are transformed into metabolic output and uncover mechanisms that regulate sweet sensitivity and sugar consumption. This area of research also has future implications for considering taste-metabolism connections in various disease models and therapeutic strategies.
