Neural determinants on meal size in invertebrate models of obesity

PROJECT SUMMARY During eating animals modulate the size of meals by associating sensory cues with rewarding qualities of food. This process is central to the control of food intake and is impaired in humans and animals exposed to high fat and sugar diets. The neural mechanisms through which food associations 1) regulate meal size and 2) are perturbed by this dietary environment, however, remain poorly understood. This lack of knowledge has hindered progress in uncovering the underlying causes of obesity and, thus, in curbing the spread of metabolic disease. Here we propose to use the D. melanogaster model to address the need for mechanistic studies on the neural regulation and deregulation of meal size. A diet high in sugar promotes higher intake and obesity in flies, but unlike vertebrate models, the neural circuits involved in food associations converge onto a single brain region; further, transgenic tools to manipulate and visualize these circuits are publicly available, thanks to decades of research and the connectome. Our long term goal is to use the unique advantages of the fly model to uncover how food environments high in sugar and fat promote obesity and metabolic disease. Our central hypothesis is that diet-driven changes in dopamine transmission underlie the increase in meal size observed in animals fed high-calorie diets. This hypothesis is based on our published and unpublished data showing a causal link between the dopaminergic processing of taste and nutrient qualities, the formation of food associations, and intake. To test this idea we will use in vivo imaging of calcium and dopamine signals, behavioral assays, metabolic measurements, and optogenetic manipulations of dopaminergic, associative learning, and premotor circuits to define both the causes of impaired food associations (Aim 1) and their consequences on meal size (Aim 2). The successful completion of the proposed studies will define how food associations control intake and the extent through which diet-dependent alterations in DA signaling impact this process; this will illuminate the neural mechanisms that regulate meal size and uncover how they are deregulated by the food environment. Together, this will help advance our understanding of the causes of obesity, which is key to the NIDDK mission of decreasing the burden and spread of metabolic disease.