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）：营养食品含量的评估对于大多数动物的能量代谢和摄食行为的调节至关重要。模型系统果蝇和哺乳动物共享迄今为止已表征的许多营养传感途径。例如，果蝇和哺乳动物响应于食物尤其是碳水化合物的消耗而释放胰岛素或胰岛素样肽。同样，它们可以感知食物中的氨基酸和蛋白质，并且它们都有抑制进食氨基酸混合物或缺乏一种或多种必需氨基酸的蛋白质的能力。 营养物质主要由胃肠系统感知，但也由大脑感知。例如，许多哺乳动物下丘脑神经元可以感知外部葡萄糖浓度的变化，但它们在调节摄食和代谢方面的功能却知之甚少。我们研究的长期目标是使用果蝇作为模型系统，识别和表征感知大脑中营养物质并传播这些事件以调节摄食和能量代谢的分子和神经解剖学成分。 我们最近在果蝇大脑中发现味觉受体 43a (Gr43a) 是一种新型的生电营养传感器。 Gr43a 与果糖密切相关。摄入碳水化合物后，血淋巴中的果糖浓度增加数倍，然后导致少量表达 Gr43a 的脑神经元被激活。行为实验表明，Gr43a 以饱足依赖性方式调节进食行为：在饥饿的果蝇中，它促进进食，而在饱足的果蝇中，它抑制进食。这些观察结果使我们提出，果糖对 Gr43a 的刺激会激活神经通路，该神经通路受到饱足依赖性信号的调节，从而产生不同的进食行为。为了阐明 Gr43a 激活的相反行为结果的机制，有必要确定导致 Gr43a 激活的信号事件 作用于大脑中 Gr43a 的下游，并识别与 Gr43a 大脑神经元进行通信的神经元目标。根据初步数据，我们提出 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直系同源物）传递其活性。此外，我们还确定了 Gr43a 活性的其他几个候选效应子和调节子，我们将使用分子遗传学方法来确定它们在摄食促进和抑制中的具体作用。最后，我们将通过表征 crzR 表达神经元并识别其目标来扩展 Gr43a 大脑感觉神经元激活的神经回路。这些研究将为新型生电营养传感器的分子和细胞逻辑提供框架，该传感器可以通过饱腹感信号进行调节以产生相反的行为输出。