Lateral Hypothalamic circuit dysfunction underlying the development of diet-induced obesity

下丘脑外侧回路功能障碍是饮食引起的肥胖发生的基础

基本信息

批准号：
10716539
负责人：
Mark Allen Rossi
金额：
$ 43.5万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716539
关键词：
Ablation Acute Address Affect Appetitive Behavior Area Body Weight Body Weight decreased Brain Calcium Central Nervous System Chronic Data Desire for food Development Diet Dissection Eating Eating Disorders Electric Stimulation Electrophysiology (science)Exhibits Feeding behaviors Food Functional disorder Future Genetic Transcription Glucose Glucose Intolerance Glutamates Goals Holography Homeostasis Human Hyperactivity Hyperphagia Hypothalamic structure Image Impairment Intake Laboratories Lateral Lateral Hypothalamic Area Measures Mediating Mediator Metabolic Metabolic Diseases Metabolism Microscopy Modeling Molecular Monitor Mus Nervous System control Neuronal Dysfunction Neurons Non-Insulin-Dependent Diabetes Mellitus Nutritional Obese Mice Obesity Optics Overnutrition Pathogenesis Pathology Peripheral Phenotype Population Regulation Resolution Role Satiation Signal Transduction Slice Structure Synapses Synaptic plasticity Testing Tetanus Toxin Therapeutic Intervention Weight Gain Work adverse outcome behavioral impairment cell type design diet-induced obesity dietary control experimental study feeding food consumption hindbrain in vivo in vivo imaging insight multi-photon multiphoton imaging new therapeutic target novel obesity development obesity treatment obesogenic restoration single cell mRNA sequencing targeted treatment two-photon

Ablation Acute Address Affect Appetitive Behavior Area Body Weight Body Weight decreased Brain Calcium Central Nervous System Chronic Data Desire for food Development Diet Dissection Eating Eating Disorders Electric Stimulation Electrophysiology (science)Exhibits Feeding behaviors Food Functional disorder Future Genetic Transcription Glucose Glucose Intolerance Glutamates Goals Holography Homeostasis Human Hyperactivity Hyperphagia Hypothalamic structure Image Impairment Intake Laboratories Lateral Lateral Hypothalamic Area Measures Mediating Mediator Metabolic Metabolic Diseases Metabolism Microscopy Modeling Molecular Monitor Mus Nervous System control Neuronal Dysfunction Neurons Non-Insulin-Dependent Diabetes Mellitus Nutritional Obese Mice Obesity Optics Overnutrition Pathogenesis Pathology Peripheral Phenotype Population Regulation Resolution Role Satiation Signal Transduction Slice Structure Synapses Synaptic plasticity Testing Tetanus Toxin Therapeutic Intervention Weight Gain Work adverse outcome behavioral impairment cell type design diet-induced obesity dietary control experimental study feeding food consumption hindbrain in vivo in vivo imaging insight multi-photon multiphoton imaging new therapeutic target novel obesity development obesity treatment obesogenic restoration single cell mRNA sequencing targeted treatment two-photon

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项目摘要

Project Summary The brain is a critical mediator of energy homeostasis, and neurocircuit dysfunction is thought to underlie obesity pathogenesis. Within the brain, the lateral hypothalamic area (LHA) exerts control over feeding behavior and body weight. Because of its considerable molecular and functional complexity, the role of LHA neurons in the development of diet-induced obesity (DIO) is still poorly understood. Addressing the LHA mechanisms governing feeding behavior and how they are remodeled during DIO will help to develop more targeted therapeutic interventions for obesity. Our overarching goal is to gain a mechanistic understanding of LHA neuronal dysfunction in DIO. Our previous work has demonstrated that the two most abundant cell types in the LHA— glutamatergic (LHAGlut) and GABAergic (LHAGABA) neurons—are transcriptionally remodeled by DIO. LHAGlut and LHAGABA neurons functionally oppose one another: LHAGlut neurons suppress feeding and reduce body weight, whereas LHAGABA neurons promote feeding and increase body weight. Our preliminary data confirm that LHAGlut and LHAGABA neurons show opposing changes in activity during acute manipulations of energy state and exhibit opponent transcriptional changes during DIO. These results highlight a potential role for LHA neuron dysfunction as a cause for overeating and DIO. However, the mechanisms underlying LHAGlut and LHAGABA neuron dysfunction in DIO are unknown. One factor that influences energy homeostasis, feeding behavior, and LHA activity is glucose. We therefore hypothesize that alterations in responsivity to glucose contribute to LHAGlut and LHAGABA neuron dysfunction in acute and chronic overnutrition and that restoration of LHA neuron activity can reverse the metabolic and behavioral impairments observed in DIO. To test this, we will determine the temporal dynamics of LHAGlut and LHAGABA neuron remodeling in DIO using longitudinal multiphoton in vivo imaging and electrophysiology. We will then test the hypothesis that glucose changes the activity of LHAGlut and LHAGABA neurons in vivo after acute and chronic overfeeding. Finally, we will test the hypothesis that restoration of LHAGlut and LHAGABA neuron activity can reverse the adverse consequences of chronic overnutrition. The results of this project will advance our conceptual understanding of the brain's involvement in DIO and identify novel therapeutic targets for the treatment of eating disorders and obesity.

项目摘要大脑是能量稳态的关键介体，神经电路功能障碍被认为是肥胖症的基础发病。在大脑内，下丘脑区域（LHA）对喂养行为和体重。由于其考虑分子和功能复杂性，LHA神经元在饮食引起的肥胖症（DIO）的发展仍然很少了解。解决LHA机制管理喂养行为及其在DIO期间的重塑方式将有助于开发更多针对性的治疗肥胖的干预措施。我们的总体目标是获得对LHA神经元的机械理解 DIO功能障碍。我们以前的工作表明，LHA中的两种最丰富的细胞类型 - 谷氨酸能（Lhaglut）和Gabaergic（Lhagaba）神经元 - 由DIO进行了转录重塑。 lhaglut和 lhagaba神经元在功能上相反：lhaglut神经元抑制喂养并减轻体重， lhagaba神经元促进喂养并增加体重。我们的初步数据证实了lhaglut lhagaba神经元在能量状态和展览的急性操纵过程中表现出相反的活动变化 DIO期间的期权转录更改。这些结果突出了LHA神经元功能障碍的潜在作用作为暴饮暴食和DIO的原因。但是，lhaglut和Lhagaba神经元的机制 DIO中的功能障碍是未知的。影响能量体内稳态，进食行为和LHA的一个因素活性是葡萄糖。因此，我们假设对葡萄糖的反应性改变有助于哈格卢特和急性和慢性营养不良中的Hagaba神经元功能障碍，LHA神经元活性的恢复可以逆转DIO中观察到的代谢和行为障碍。为了测试这一点，我们将确定临时性 Lhaglut和Lhagaba神经元在DIO中使用纵向多光在体内成像和电生理学。然后，我们将测试葡萄糖改变lhaglut和Lhagaba活性的假设急性和慢性过度喂养后体内神经元。最后，我们将检验lhaglut恢复的假设 lhagaba神经元活性可以扭转慢性营养的不利后果。结果的结果项目将提高我们对大脑参与DIO的概念理解，并确定新颖治疗饮食失调和肥胖症的治疗靶标。