Neural mechanisms for VGF regulation of energy balance

VGF 调节能量平衡的神经机制

基本信息

批准号：
10197299
负责人：
CHRISTOPH BUETTNER
金额：
$ 42.16万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197299
关键词：
Ablation Acute Adipocytes Adipose tissue Adrenergic Agents Adrenergic beta-Agonists Adult Astrocytes Binding Biological Blood Pressure Body Weight Brain Brain-Derived Neurotrophic Factor Brown Fat C-terminal Cell Nucleus Cells Chronic Communication Complement 3a Complement Receptor Cre driver Diabetes Mellitus Drug Targeting Endocrine Energy Metabolism Genes Heart Diseases Heart Rate Homeostasis Hypertension Hypothalamic structure Immune Innate Immune System Intervention Isoproterenol Knock-in Mouse Knockout Mice Lipolysis Liver LoxP-flanked allele Malignant Neoplasms Mediating Metabolic Microglia Modality Molecular Mus Neurons Neuropeptides Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Outcome Pathway interactions Peptides Peripheral Phenotype Physiological Prevalence Process Proteins Regulation Research Risk Factors Role Signal Pathway Signal Transduction Site Sympathetic Nervous System Testing Tissues Transgenic Organisms VGF protein blood glucose regulation carbohydrate metabolism cell type complement C3a receptor complement pathway conditional knockout designer receptors exclusively activated by designer drugs energy balance glucose metabolism insight knockout gene lipid metabolism mouse model neuromechanism neurotrophic factor new therapeutic target novel obesity treatment receptor targeted treatment

Ablation Acute Adipocytes Adipose tissue Adrenergic Agents Adrenergic beta-Agonists Adult Astrocytes Binding Biological Blood Pressure Body Weight Brain Brain-Derived Neurotrophic Factor Brown Fat C-terminal Cell Nucleus Cells Chronic Communication Complement 3a Complement Receptor Cre driver Diabetes Mellitus Drug Targeting Endocrine Energy Metabolism Genes Heart Diseases Heart Rate Homeostasis Hypertension Hypothalamic structure Immune Innate Immune System Intervention Isoproterenol Knock-in Mouse Knockout Mice Lipolysis Liver LoxP-flanked allele Malignant Neoplasms Mediating Metabolic Microglia Modality Molecular Mus Neurons Neuropeptides Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Outcome Pathway interactions Peptides Peripheral Phenotype Physiological Prevalence Process Proteins Regulation Research Risk Factors Role Signal Pathway Signal Transduction Site Sympathetic Nervous System Testing Tissues Transgenic Organisms VGF protein blood glucose regulation carbohydrate metabolism cell type complement C3a receptor complement pathway conditional knockout designer receptors exclusively activated by designer drugs energy balance glucose metabolism insight knockout gene lipid metabolism mouse model neuromechanism neurotrophic factor new therapeutic target novel obesity treatment receptor targeted treatment

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项目摘要

Body weight is controlled in large part by communication between the brain and peripheral metabolic tissues, including white and brown adipose tissue, via the sympathetic nervous system to regulate energy expenditure and lipolysis. Pharmacotherapeutic intervention to reduce adiposity, however, has been relatively unsuccessful. We have identified the neurotrophin-inducible neuronal protein VGF (non-acronymic), and one of its processed C-terminal peptides TLQP-21, as central and peripheral regulators of energy expenditure and lipolysis. TLQP-21 activates the Complement C3a Receptor 1 (C3aR1), an integral component of the innate immune system, and in adipocytes, enhances lipolysis mediated by the beta-adrenergic agonist isoproterenol. Mice with VGF ablated in the adult ventromedial hypothalamus (VMH) and arcuate (ARC) have increased adiposity and decreased energy expenditure, a phenotype that is consistent with a key physiological role for TLQP-21 in the adult CNS, one that is also congruent with many actions of brain-derived neurotrophic factor (BDNF) in the hypothalamus. Utilizing floxed (lox-p flanked) VGF and C3aR1 mouse models together with established transgenic Cre-driver lines and targeted AAV-Cre administration, we will test the hypothesis that in adults, VGF and its peptides, particularly TLQP-21, regulate energy expenditure, lipolysis, and glucose homeostasis via central modulation of sympathetic outflow from the VMH and paraventricular hypothalamus (PVH), which receives extensive VGF-containing projections from ARC/VMH, and provides essential BDNF- and VGF-containing sympathetic outflow pathways to brown adipose tissue (BAT). Two specific aims are proposed. Aim 1 will probe the roles of VGF in the CNS pathways that originate in the PVH and VMH, which can be activated by `designer receptors exclusively activated by designer drugs' (DREADD), and regulate energy expenditure, glucose metabolism and lipolysis via sympathetic outflow from hypothalamus. Aim 2 will define the site(s) of action and function(s) of the pivotal VGF-derived peptide TLQP-21, determining whether its actions in the adult CNS are dependent on C3aR1 that is expressed on neurons, microglia, and/or astrocytes. The complementary research expertise of the PIs will be essential for successful completion of our aims, providing fundamental insight into the mechanisms by which VGF, its peptide TLQP-21, and the TLQP-21 receptor C3aR1, contribute to hypothalamic-sympathetic circuits that control energy and glucose homeostasis, potentially identifying promising new drug targets for the treatment of obesity and diabetes.

体重在很大程度上通过大脑和周围代谢组织之间的通信来控制包括白色和棕色脂肪组织，通过交感神经系统调节能量消耗和脂解。但是，药物治疗干预以降低肥胖性相对较低不成功。我们已经确定了神经营养蛋白可诱导的神经元蛋白VGF（非歧义），一个其处理后的C末端肽TLQP-21，作为能量消耗的中心和外围调节剂脂解。 TLQP-21激活补体C3A受体1（C3AR1），这是先天性的组成部分免疫系统和脂肪细胞中，可以增强β-肾上腺素激动剂异丙肾上腺素介导的脂解。在成年腹侧下丘脑（VMH）和弧形（ARC）中消融的VGF的小鼠已增加肥胖和能量消耗降低，这种表型与关键生理作用一致成人中枢神经系统中的TLQP-21，这也与脑衍生的神经营养因子的许多作用一致（BDNF）在下丘脑中。利用Floxed（Lox-P侧）VGF和C3AR1小鼠模型以及建立的转基因Cre驱动器线并针对AAV-CRE给药，我们将测试以下假设。成人，VGF及其肽，尤其是TLQP-21，调节能量消耗，脂解和葡萄糖稳态通过中央调节VMH和脊髓脑膜下丘脑的交感神经流出（PVH），它从ARC/VMH接收大量含VGF的预测，并提供必需的BDNF- 和含有VGF的交感神经流出途径（BAT）。两个具体目标是建议的。 AIM 1将探测VGF在源自PVH和VMH的CNS途径中的作用，可以被“设计器药物专门激活的设计器受体”（Dreadd）激活，并调节能量消耗，葡萄糖代谢和脂解通过下丘脑的交感神经流出。 AIM 2意志定义关键VGF衍生肽TLQP-21的动作和功能的位点成年中枢神经系统的作用取决于在神经元，小胶质细胞和/或星形胶质细胞上表达的C3AR1。 PI的补充研究专业知识对于成功完成我们的目标至关重要提供有关VGF，其肽TLQP-21和TLQP-21的机制的基本见解受体C3AR1，有助于控制能量和葡萄糖稳态的下丘脑 - 同情回路，有可能识别有希望的新药物来治疗肥胖和糖尿病。