Regulation of Feeding Behavior by Brain-based Nutrient Sensors

基于大脑的营养传感器调节进食行为

• 批准号: 8719645
• 负责人: Hubert O Amrein
• 金额: $ 29.57万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719645
• 关键词: Afferent Neurons; Amino Acids; Animals; Base of the Brain; Behavioral; Behavioral Assay; Biological Assay; Biological Models; Brain; Carbohydrates; Data; Diabetes Mellitus; Diet; Drosophila genus; Drosophila melanogaster; Energy Metabolism; Essential Amino Acids; Evaluation; Event; Feeding behaviors; Food; Fostering; Fructose; Gene Expression Profile; Gene Targeting; Genes; Glucose; Gonadotropin Hormone Releasing Hormone; Hemolymph; Human; Hypothalamic structure; Image; Insulin; Investigation; Lead; Logic; Mammals; Maps; Mediating; Metabolic Diseases; Metabolism; Minor; Molecular; Molecular Genetics; Monitor; Mutation; Neural Pathways; Neurons; Neuropeptides; Neurotransmitters; Nutrient; Obesity; Operating System; Organism; Orthologous Gene; Outcome; Output; Pathway interactions; Peptides; Process; Proteins; Public Health; Regulation; Research; Role; Satiation; Signal Transduction; Structure; System; Trehalose; base; cellular targeting; detection of nutrient; feeding; fly; food consumption; gastrointestinal system; homologous recombination; insight; mutant; neural circuit; novel; public health relevance; receptor; relating to nervous system; research study; response; sensor; sugar

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.

描述（由申请人提供）：养分食品含量的评估对于大多数动物的能量代谢和喂养行为至关重要。模型系统果蝇Melanogaster和哺乳动物共享迄今为止已经表征的许多营养传感途径。例如，果蝇和哺乳动物释放胰岛素或胰岛素样肽，响应食物的消耗，尤其是碳水化合物。同样，它们可以感觉到食物中的氨基酸和蛋白质，并且具有抑制缺乏一种或多种必需氨基酸的氨基酸混合物或蛋白质的能力。 营养物质主要是通过胃肠系统感知的，也是大脑的。例如，许多哺乳动物下丘脑神经元可以感觉到外部葡萄糖浓度的变化，但是它们在调节喂养和代谢中的功能知之甚少。我们研究的长期目的是识别和表征分子和神经解剖学成分，这些成分使用果蝇作为模型系统，这些成分感知大脑中的营养并传播这些事件以调节喂养和能量代谢。 我们最近将味觉受体43A（GR43A）鉴定为果蝇脑中的一种新颖的电源营养传感器。 GR43A被狭窄地调到糖果糖。碳水化合物进食后，血淋巴中的果糖浓度增加了几倍，从而导致少数GR43A表达脑神经元的激活。行为实验表明，GR43A以饱食的方式调节喂养行为：在饥饿的苍蝇中，它促进喂食，而在饱受果蝇中，它会抑制它。这些观察结果使我们提出果糖刺激的GR43A刺激激活了神经途径，该途径由依赖性信号调节以产生不同的喂养行为。为了阐明GR43A激活的相反行为结果的机制，必须确定信号事件至关重要 在大脑中GR43A的下游ACT，并确定GR43A脑神经元传达的神经元靶标。根据初步数据，我们建议GR43A脑神经元通过神经肽Corazonin（哺乳动物促性腺激素释放激素的功能性直系同源物）传递其活性。此外，我们已经确定了GR43A活性的其他几个候选效应子和调节剂，我们将使用分子遗传方法来确定它们在进食促进和抑制中的特定作用。最后，我们应通过表征表达神经元并识别其靶标的CRZR来扩展由GR43A脑感觉神经元激活的神经回路。这些研究将为新型的电源营养传感器的分子和细胞逻辑提供一个框架，可以通过饱腹信号调节以产生相反的行为输出。