Eating behavior is influenced by multiple factors such as nutritional needs and food palatability, which makes it difficult to investigate how this behavior is regulated. Peripheral chemosensory neurons such as sugar receptor neurons endow animals to detect palatable food. Additional mechanisms would exist for the detection of foods that meet nutrient needs. Indeed, my laboratory showed that the Drosophila mutants - GR5a;GR64a and pox-neuro mutants - that are insensitive to the taste of sugar still developed a preference for a sugar solution based on its nutritional value after prolonged periods of food deprivation. Specifically, these starved sugar-blind or taste-blind flies were able to distinguish nutritious D-glucose from zero-calorie L-glucose, which tastes almost identical as D-glucose to flies. These findings suggest that there exists a taste-independent, internal sugar sensor that detects its caloric content. Using two-choice preference assay (D-glucose versus L-glucose), we carried out a small-scale screen for an internal sugar sensor and identified a mutation in a Sodium/Glucose co-transporter, dSGLT3, that was completely insensitive to the caloric content of sugar, but rather responded only to the concentration of sugar - the """"""""sweetness"""""""". Surprisingly, dSGLT3 is expressed in 10 pairs of neurons in the brain that are required for internal sugar sensing. In this proposal, we will characterize the function of dSGLT3 gene and dSGLT3+ expressing neurons in mediating internal sugar sensing by conducting behavior, electrophysiology and calcium imaging experiments in Drosophila. These studies will not only fundamentally transform our understanding of chemosensory biology, but will also provide a valuable framework for understanding the mechanisms by which appetite is regulated by metabolic needs in normal, obese and eating disorder patients.
The internal sugar sensing mechanism we propose to investigate in Drosophila is likely to regulate eating behavior in humans as there exist over a dozen SGLTs belonged to this family in our genome. Therefore, elucidating the function of dSGLT3 as an internal sugar sensor in the fly brain would not only provide a valuable framework for understanding how appetite is regulated by metabolic needs, but could lead to development of therapeutic application to treat obesity and eating disorders. Obese individuals might be insensitive in detecting the heightened circulating sugar levels after meals and therefore, continue to eat. Conversely, anorexic patients may have highly sensitive internal sugar sensors. As consequence, they always feel sated and are reluctant to eat. We could target and manipulate the function of SGLT in obese or anorexic patients by treating them with the SGLT antagonists or agonists. Indeed, injection of a SGLT antagonist, phlorizin, into the cerebrospinal fluid increases food intake (1, 2). Anorexic patients might respond to phlorizin, particularly if their SGLT or SGLT pathway contributes to the cause of this disorder. In addition to phlorizin, new drugs that easily cross the blood-brain barrier could be developed to target the SGLT in the brain. Furthermore, this study would pilot a tantalizing medical inquiry - whether there exist polymorphisms or mutations in the SGLT locus of eating disorder patients and morbidly obese family. 1. Z. Glick, J. Mayer, Hyperphagia caused by cerebral ventricular infusion of phloridzin. Nature 219, 1374 (Sep 28, 1968). 2. S. Tsujii, G. A. Bray, Effects of glucose, 2-deoxyglucose, phlorizin, and insulin on food intake of lean and fatty rats. Am J Physiol 258, E476 (Mar, 1990). !
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