DESCRIPTION (provided by applicant): Evaluation of nutrient food content is essential for the regulation of energy metabolism and feeding behavior in most animals. The model system Drosophila melanogaster and mammals share many of the nutrient sensing pathways that have been characterized thus far. For example, Drosophila and mammals release insulin or insulin-like peptides in response to the consumption of food, especially carbohydrates. Likewise, they can sense amino acids and proteins in food, and they share an ability to suppress feeding on amino acid mixtures or proteins that lack one or more essential amino acids. Nutrients are sensed mostly by the gastrointestinal system, but also by the brain. For example, numerous mammalian hypothalamic neurons can sense changes in external glucose concentration, but their function in the regulation of feeding and metabolism are poorly understood. The long-term objective of our research is to identify and characterize the molecular and neuroanatomical components that sense nutrients in the brain and propagate these events to regulate feeding and energy metabolism, using Drosophila as a model system. We recently identified the Gustatory receptor 43a (Gr43a) as a novel, electrogenic nutrient sensor in the Drosophila brain. Gr43a is narrowly tuned to the sugar fructose. Upon carbohydrate feeding, fructose concentration in the hemolymph increases several fold, which then leads to the activation of a small number of Gr43a expressing brain neurons. Behavioral experiments showed that Gr43a regulates feeding behavior in a satiation dependent manner: in hungry flies, it promotes feeding, while in satiated flies, it suppresses it. These observations lead us to propose that Gr43a stimulation by fructose activates a neural pathway, which is modulated by a satiation-dependent signal to generate distinct feeding behaviors. To elucidate the mechanism of the opposing behavioral outcomes of Gr43a activation, it will be essential to identify the signaling events that act downstream of Gr43a in the brain, and to identify the neuronal targets with which the Gr43a brain neurons communicate. Based on preliminary data, we propose that Gr43a brain neurons transmit their activity via the neuropeptide corazonin, the functional ortholog of mammalian gonadotropin releasing hormone. In addition, we have identified several other candidate effectors and modulators of Gr43a activity, and we shall use molecular genetic approaches to determine their specific roles in feeding promotion and suppression. Finally, we shall expand the neural circuitry activated by the Gr43a brain sensory neurons by characterizing crzR expressing neurons and identifying their targets. These studies will provide a framework for the molecular and cellular logic of a novel electrogenic nutrient sensor, which can be modulated by satiety signals to generate opposing behavioral outputs.

PUBLIC HEALTH RELEVANCE: This research is relevant to public health because it will lead to the discovery of novel mechanisms that regulate and modulate feeding behavior. Using Drosophila as a powerful model system, our research has identified fructose and its narrowly tuned receptor in the brain, Gr43a, as central components of an internal nutrient sensing system. Significantly, fructose is also a minor, low abundant sugar in humans (and other mammals), and dietary fructose is differently metabolized than dietary glucose. However, it is not known how fructose is monitored internally in humans or any other mammal. Thus, our research will establish basic concepts for how brain-based nutrient sensing systems operate, and we believe it will foster similar investigations in fructose sensing in mammals, providing potentially important new insights into the basis of metabolic diseases, diabetes and obesity.