Neural mechanisms for VGF regulation of energy balance

VGF 调节能量平衡的神经机制

• 批准号: 10208870
• 负责人: CHRISTOPH BUETTNER
• 金额: $ 55.67万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208870
• 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

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.

体重在很大程度上是由大脑和周围代谢组织之间的通讯控制的， 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 和脂解作用。然而，减少肥胖的药物干预相对较少。 不成功。我们已经确定了神经营养因子诱导的神经元蛋白VGF（非首字母缩写）， 其加工的C-末端肽TLQP-21，作为能量消耗的中枢和外周调节剂， 脂肪分解TLQP-21激活补体C3 a受体1（C3 aR 1），这是先天免疫缺陷的组成部分。 在免疫系统和脂肪细胞中，增强由β-肾上腺素能激动剂异丙肾上腺素介导的脂解作用。 在成年下丘脑腹内侧（VMH）和弓状核（ARC）中切除VGF的小鼠， 肥胖和能量消耗减少，这是一种与肥胖的关键生理作用一致的表型。 TLQP-21在成人中枢神经系统中，也与脑源性神经营养因子的许多作用一致 （BDNF）在下丘脑。使用floxed（lox-p侧翼）VGF和C3 aR 1小鼠模型， 建立的转基因Cre驱动系和靶向AAV-Cre施用，我们将检验以下假设： 在成年人中，VGF及其肽，特别是TLQP-21，调节能量消耗、脂解和葡萄糖 通过中枢调节VMH和室旁下丘脑交感神经流出的稳态 (PVH)，它从ARC/VMH接受广泛的含VEGF的投射，并提供必需的BDNF- 和含VEGF的交感神经流出途径至棕色脂肪组织（BAT）。两个具体目标是 提出了目的1探讨VGF在起源于PVH和VMH的CNS通路中的作用， 可以被“专门由设计药物激活的设计受体”（DREADD）激活，并调节 能量消耗、葡萄糖代谢和通过下丘脑交感神经流出的脂解。目标2将 定义关键的VEGF衍生肽TLQP-21的作用位点和功能，确定其是否 在成人CNS中的作用依赖于在神经元、小胶质细胞和/或星形胶质细胞上表达的C3 aR 1。 研究所的互补研究专长对成功实现我们的目标至关重要， 提供了VGF及其肽TLQP-21和TLQP-21与VGF相互作用的机制的基本见解。 受体C3 aR 1，有助于控制能量和葡萄糖稳态的下丘脑-交感神经回路， 潜在地鉴定用于治疗肥胖症和糖尿病的有前景的新药靶点。