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通过大脑和周围代谢组织之间的沟通来控制的， 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 还有脂肪分解。然而，减少肥胖症的药物治疗干预相对来说 不成功。我们已经鉴定了神经营养素诱导的神经元蛋白VGF(非缩写)，以及一种 其加工的C端肽TLQP-21作为能量消耗的中枢和外周调节因子，以及 脂肪分解。TLQP-21激活补体C3a受体1(C3aR1)，补体C3a受体1(C3aR1)是天然的 免疫系统和脂肪细胞可增强由β-肾上腺素能激动剂异丙肾上腺素介导的脂肪分解。 成年小鼠下丘脑腹内侧部(VMH)和弓状核(ARC)的VGF消融后，小鼠的VGF含量增加 肥胖和能量消耗减少，这一表型与 TLQP-21在成人中枢神经系统中的表达，与脑源性神经营养因子的许多作用相一致 (脑源性神经营养因子)在下丘脑。利用有牙线的(lox-p侧翼)VGF和C3aR1小鼠模型 建立了转基因Cre驱动系并靶向注射AAV-Cre，我们将检验以下假设：在 成人，VGF及其多肽，特别是TLQP-21，调节能量消耗、脂解和血糖 中枢调节下丘脑和下丘脑室旁核交感神经流出的动态平衡 (PVH)，它从ARC/VMH接收包含VGF的广泛投影，并提供必要的BDNF- 和含有VGF的交感神经流出通路至棕色脂肪组织(BAT)。两个具体目标是 建议。目标1将探讨VGF在起源于PVH和VMH的中枢神经系统通路中的作用。 能被‘设计师受体’(DREADD)激活，并调节 能量消耗、葡萄糖代谢和通过交感神经流出下丘脑的脂肪分解。目标2将 确定血管生长因子衍生肽TLQP-21的作用部位(S)和功能部位(S)，确定其是否具有 成年中枢神经系统的活动依赖于表达在神经元、小胶质细胞和/或星形胶质细胞上的C3aR1。 私人投资主任的研究专业知识相辅相成，对成功完成我们的目标至为重要。 为VGF及其多肽TLQP-21和TLQP-21的作用机制提供了基本的见解 受体C3aR1参与控制能量和葡萄糖动态平衡的下丘脑-交感神经回路， 有可能确定治疗肥胖症和糖尿病的有前途的新药靶点。