Characterization of Taste-independent Sugar Sensor in the Brain

描述(申请人提供)：饮食行为受到多种因素的影响，如营养需求和食物适口性，这使得很难调查这种行为是如何被调节的。外周化学感受器神经元，如糖感受器神经元，赋予动物检测美味食物的能力。将有更多的机制来检测满足营养需求的食品。事实上，我的实验室表明，对糖的味道不敏感的果蝇突变体--GR5a、GR64a和POX-NERO突变体--在长时间的食物匮乏后，仍然根据糖液的营养价值产生了对糖液的偏好。具体地说，这些饥饿的糖盲或味盲的果蝇能够区分营养的D-葡萄糖和零卡路里的L葡萄糖，对果蝇来说，后者的味道几乎与D-葡萄糖相同。这些发现表明，存在一种不依赖味道的内部糖传感器，可以检测其卡路里含量。使用双选择偏好试验(D-葡萄糖和L-葡萄糖)，我们对内部糖传感器进行了小规模筛选，发现了钠/葡萄糖共转运体dSGLT3的一个突变，该突变对糖的热量含量完全不敏感，而只对糖的浓度--“甜度”--做出反应。令人惊讶的是，dSGLT3在大脑中10对神经元中表达，这些神经元是内部糖感所必需的。在这项研究中，我们将通过对果蝇进行行为学、电生理学和钙成像实验，研究dSGLT3基因和dSGLT3+表达神经元在介导内源性糖感觉中的作用。这些研究不仅将从根本上改变我们对化学感觉生物学的理解，而且还将为理解正常、肥胖和进食障碍患者的代谢需求调节食欲的机制提供一个有价值的框架。 与公共健康相关：我们计划在果蝇中研究的内部糖感应机制可能会调节人类的饮食行为，因为在我们的基因组中存在十几个属于这个家族的SGLT。因此，阐明dSGLT3作为果蝇脑内糖感受器的功能不仅将为了解代谢需求如何调节食欲提供有价值的框架，而且可能有助于开发治疗肥胖症和饮食失调的治疗应用。肥胖的人可能对餐后循环血糖水平升高的检测不敏感，因此继续进食。相反，厌食症患者可能有高度敏感的内部血糖传感器。结果，他们总是觉得饱了，不愿吃东西。我们可以通过使用SGLT拮抗剂或激动剂来靶向和操纵肥胖或厌食症患者的SGLT功能。事实上，在脑脊液中注射SGLT拮抗剂根茎苷可增加食物的摄入量(1，2)。厌食症患者可能对根茎苷有反应，特别是如果他们的SGLT或SGLT途径与这种疾病的原因有关。除了鬼针草苷，还可以开发出容易跨越血脑屏障的新药，以靶向大脑中的SGLT。此外，这项研究还将尝试一项诱人的医学调查--进食障碍患者和病态肥胖家庭的SGLT基因是否存在多态或突变。1.Z.Glick，J.Mayer，脑室注射根皮苷引起的吞噬功能亢进。《自然》219,1374(1968年9月28日)。2.S.Tsujii，G.A.Bray，葡萄糖、2-脱氧葡萄糖、根茎苷和胰岛素对瘦大鼠和肥胖大鼠食物摄入量的影响。Am J Physiol258，E476(1990年3月)。好了！

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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). !