Due in part to the rise in the worldwide incidence of obesity and diabetes, the molecular mechanisms regulating feeding behavior have received much attention. However, despite the tremendous increases in our understanding of how food intake and metabolism are coordinated, very little is known about the neural circuits and genes underlying feeding. Furthermore, how signals from both metabolic (to replenish energy) and hedonic (for reward) feeding circuits are integrated to regulate food intake and food choice remain unclear. While much has been learned from mammalian model organisms, very few genes involved in feeding behavior and energy homeostasis have been identified because of the difficulty in performing genetic screens in these models. Thus, using a genetically amenable model organism such as the fruit fly provides an ideal strategy to complement mammalian research. During my postdoctoral studies I developed an assay to study food choice behavior in Drosophila and found that flies are equipped with a mechanism to detect the nutritional value of food independently of taste. Specifically, food-deprived flies prefer calorie-rich sugars to zero-calorie sweeteners. Through genetic and behavioral screens, I identified a conserved gene that is required for flies to make metabolic feeding choices. This gene, a candidate Drosophila Sodium-Glucose-Transporter (dSGLT) is expressed in a small subset neurons in the fly brain. My hypothesis is that dSGLT regulates food choice by monitoring glucose levels in the blood. Indeed, homologues of this gene expressed in the mammalian hypothalamus are thought to play an active role in responding to changing glucose levels by affecting the excitability of neurons, but their role in feeding is not known. As defects in neural sensing of glucose in the hypothalamus have been shown to play a role in the development of obesity and contribute to type-2 diabetes, it is of the utmost importance to better understand the molecular mechanism of glucosensation underlying feeding and metabolism. In this proposal I present a focused strategy to characterize the function of the fly candidate dSGLT in glucose-sensation and behavior. I will determine if dSGLT is a glucose sensor and how it confers glucosensing properties to the neurons that express it. I will analyze if the neural circuit expressing this gene is necessary and sufficient for the choice for metabolizable sugars, and how the dynamics of glucosensation in these neurons modulate food choice behavior. Finally, I will conduct two targeted genetic screens: one to identify other genes involved downstream of glucosensing in dSGLT neurons and the other to identify the neuropeptides and neuropeptide circuits downstream of SGLT neurons that mediate the effector mechanisms ultimately regulating food choice. These studies will provide insights into the molecular mechanisms of glucosensation and its role in feeding. They will also provide mammalian researchers with conserved genes to use as molecular and neurochemical markers in future studies of glucosensation, feeding, and disease.
Neurons in the mammalian brain respond to changing concentration of extracellular glucose by varying their firing rates. This process, also known as glucose sensation is thought to play an important role in the regulation of sleep-wake cycles, metabolism, and feeding. In particular, defects in glucose-sensation in the hypothalamus play a role in obesity and the development of type-2 diabetes. The lack of specific molecular and neurochemical markers to identify subsets of glucosensing cells, and the absence of exhaustive studies, from behavior to physiology, has hindered our understanding on the role of glucosensing neurons in feeding and homeostasis. Because done in a genetically amenable model organism like the fruit fly, our studies will produce fundamental insights into the genes and circuits involved in glucosensation. Furthermore, thanks to the wealth of behavioral genetic tools available in Drosophila, the effect of these genes can be directly tested on behavior. Thus, we are confident that our studies will identify both genes involved directly in glucosensation and those downstream of it, like neuropeptides, that ultimately modulate feeding. Furthermore, if successful, the outlined research could provide targeted therapeutics to treat defects in glucosensation that are involved in obesity, diabetes or other metabolic diseases. (Note: The critiques below were prepared by the reviewers assigned to this application. These commentaries and criterion scores do not necessarily reflect the position of the authors at the close of the group discussion, nor the final majority opinion of the group, although reviewers are asked to amend their critiques and criteria scores if their position changed during the discussion. The resume and other initial sections of the summary statement are the authoritative representation of the final outcome of group discussion. If there is any discrepancy between the peer reviewers'commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion.)