Understanding the role of the brain CRH (Corticotropin-Releasing Hormone) system in the detection and consumption of nutritional sugar.

了解大脑 CRH（促肾上腺皮质激素释放激素）系统在营养糖检测和消耗中的作用。

• 批准号: 9070673
• 负责人: GREG S.B. SUH
• 金额: $ 38.14万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070673
• 关键词: 5' -AMP-activated protein kinase; Animal Feed; Animals; Axon; Behavioral Assay; Biological Assay; Brain; Calcium; Cells; Consumption; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Coupled; Defecation; Dendrites; Desire for food; Detection; Digestion; Diuretics; Dorsal; Drosophila genus; Eating; Eating Disorders; Environment; Esophageal; Esophagus; Excretory function; Feedback; Feeding behaviors; Food; Food Processing; Food deprivation (experimental); Foundations; Frequencies; Gastric Emptying; Genes; Glucose; Glucose Transporter; Goals; Hindgut; Homologous Gene; Hormones; Hypoglycemia; Hypothalamic structure; Image; Individual; Ingestion; Interneurons; L-Glucose; Label; Laboratories; Life; Locomotion; Mammals; Mediating; Modality; Modeling; Motor Neurons; Movement; Mus; Nature; Nerve; Neurons; Neuropeptides; Neurosecretory Systems; Nutritional; Obesity; Pathway interactions; Patients; Peptides; Peripheral; Physiological; Play; Process; Property; RRM2 gene; Reflex action; Regulation; Research; Rodent; Role; Sequence Homology; Signaling Molecule; Starvation; Stomach; Sweetening Agents; System; Taste Buds; Taste Perception; Techniques; Technology; Testing; Time; behavioral response; biological adaptation to stress; blood glucose regulation; cell motility; conditioning; counterregulation; enantiomer; feeding; fly; hexokinase; in vivo; mutant; postsynaptic neurons; preference; public health relevance; receptor; research study; sensor; sugar; sweet taste perception

 DESCRIPTION (provided by applicant): Sugar in the natural environment can be detected through taste-independent and taste-dependent modalities. Taste-independent modalities consist mainly of peripheral chemosensory neurons such as sweet taste receptors, which primarily detect the orosensory value of sugar (i.e. sweetness). My laboratory and others have shown that there exist taste-independent, internal sensors that detect the nutritional value of sugar in Drosophila and rodents. In this proposal, we will test a hypothesis that six neurons in the fly brain that produce diuretic hormone (Dh44), a homologue of the mammalian corticotropin-releasing hormone (CRH), directly detects the nutritional content of sugar in a fast time scale. Our preliminary results indicate that DH44 neurons are required for the selection of nutritive sugars in the two-choice assay and are activated by nutritive D-glucose, but not by nonnutritive L-glucose in calcium imaging experiment. Furthermore, we made a surprising observation that artificial activation of DH44 pathway resulted in rapid extensions of the mouthpart, and frequent episodes of excretion. These actions would facilitate the ingestion and digestion of nutritive foods. In the proposal, we will also determine the mechanism by which the activation of DH44 pathway leads to a rapid increase of ingestion and digestion through a positive feedback loop to continue consumption of nutritive foods. Identification and characterization of the taste-independent sugar sensor in Drosophila would provide a framework to understand how appetite is regulated by energy need in normal and eating disorder patients. Given its strong sequence homology, CRH and its neurons in the hypothalamus may offer similar functions in mammals. RELEVANCE: The proposed study to investigate the function of six neurons in the Drosophila brain that produce diuretic hormone (Dh44), a homologue of the mammalian corticotropin-releasing hormone (CRH), suggests a hypothesis that CRH neurons in the hypothalamus function as internal sensors that detect the nutritional value of sugar. Indeed, CRH was shown to play a significant role in the regulation of feeding and food intake, but the exact nature of it role is controversial. The homology between Drosophila DH44 and mammalian CRH is approximately 30% and between Drosophila and mammalian receptors is approximately 40%. Similar to Drosophila DH44, mammalian CRH regulates gastric and colonic movements, and stimulates defecation in rodents. CRH also mediates glucose homeostasis by regulating hypoglycemia-induced counterregulation. It was suggested that the function of glucose-sensing neurons is to generate neuroendocrine stress responses to the hypoglycemic challenge, but the identity of these neurons is unknown. It is possible that CRH neurons in the hypothalamus are glucose-sensing neurons as in the Drosophila brain and are capable of mediating starvation-induced behavioral responses to the nutritional value of sugar in mammals. Mice with compromised CRH function are indeed obese or anorexic. It is intriguing to speculate that obese individuals may be insensitive to the heightened circulating sugar levels after meals and therefore, continues to eat. By contrast, anorexic individuals may be too sensitive to circulating sugar levels and therefore, feel satiated and are reluctant to eat. The proposed research using the Drosophila model would provide a foundation for understanding the mechanisms by which internal sensors respond to the nutritional value of sugar in normal and obese individuals.

 描述（由申请人提供）：天然环境中的糖可以通过味道独立和味道依赖的方式检测。味觉独立的形式主要由外周化学感觉神经元如甜味受体组成，其主要检测糖的口腔感觉值（即甜味）。我的实验室和其他实验室已经证明，在果蝇和啮齿动物中存在独立于味觉的内部传感器，可以检测糖的营养价值。在这项提案中，我们将测试一个假设，即在苍蝇大脑中产生利尿激素（Dh 44），哺乳动物促肾上腺皮质激素释放激素（CRH）的同系物，直接检测糖的营养成分在一个快速的时间尺度。我们的初步结果表明，DH 44神经元是必需的选择营养糖的二次选择试验和激活的营养D-葡萄糖，但不被非营养L-葡萄糖钙成像实验。此外，我们还发现了一个令人惊讶的现象，即人工激活DH 44通路会导致口器的快速延伸和频繁的排泄。这些作用将促进营养食物的摄取和消化。在该提案中，我们还将确定DH 44通路的激活通过正反馈回路导致摄入和消化快速增加以继续食用营养食物的机制。在果蝇中识别和表征味觉无关的糖传感器将提供一个框架，以了解正常和饮食失调患者的能量需求如何调节食欲。由于其强的序列同源性，CRH及其下丘脑神经元可能在哺乳动物中提供类似的功能。 相关性：拟研究果蝇脑中产生利尿激素（Dh 44）（哺乳动物促肾上腺皮质激素释放激素（CRH）的同系物）的6个神经元的功能，提出了一个假设，即下丘脑中的CRH神经元作为检测糖的营养价值的内部传感器发挥作用。事实上，CRH在调节摄食和食物摄入方面发挥着重要作用，但其作用的确切性质存在争议。果蝇DH 44与哺乳动物CRH之间的同源性约为30%，果蝇与哺乳动物受体之间的同源性约为40%。与果蝇DH 44类似，哺乳动物CRH调节胃和结肠运动，并刺激啮齿动物排便。CRH还通过调节低血糖诱导的反调节来介导葡萄糖稳态。有人认为，葡萄糖敏感神经元的功能是产生神经内分泌应激反应的低血糖的挑战，但这些神经元的身份是未知的。下丘脑中的CRH神经元可能与果蝇脑中的一样是葡萄糖敏感神经元，并且能够介导哺乳动物对糖的营养价值的饥饿诱导的行为反应。CRH功能受损的小鼠确实肥胖或肥胖。有趣的是，推测肥胖个体可能对餐后循环糖水平升高不敏感，因此继续进食。相比之下，肥胖者可能对循环糖水平过于敏感，因此感到饱足，不愿进食。使用果蝇模型的拟议研究将为理解正常和肥胖个体内部传感器对糖的营养价值做出反应的机制提供基础。