Molecular dissection of TLQP-21 peptide functions in obesity

TLQP-21 肽在肥胖中的功能的分子解析

基本信息

批准号：
8747209
负责人：
Alessandro Bartolomucci
金额：
$ 32.75万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-06 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8747209
关键词：
Achievement Adenylate Cyclase Adipocytes Adipose tissue Adrenergic Receptor Adverse effects Agonist Behavior Binding Biological Calcium Cardiovascular Diseases Cardiovascular system Chinese Hamster Ovary Cell Chronic Complement 3a Cyclic AMP Development Diabetes Mellitus Diabetic mouse Diet Disease Dissection Engineering Enteral Epidemiology Failure Fatty acid glycerol esters Figs - dietary Forskolin Future G-Protein-Coupled Receptors Genes Genotype Health Hot Spot Human Hypertension Immunity In Vitro Isoproterenol Knockout Mice Knowledge Lipolysis Malignant Neoplasms Mediating Membrane Modeling Molecular Molecular Mechanisms of Action Mus Myeloid Cell Activation Names Nerve Non-Insulin-Dependent Diabetes Mellitus Nutrient Obese Mice Obesity Outcome Peptides Pharmacological Treatment Phenotype Physiological Primates Publishing Risk Risk Factors Rodent Role Signal Transduction Signaling Molecule Sympathomimetics System Testing Therapeutic Weight absorption base energy balance feeding improved mutant novel novel strategies novel therapeutics pandemic disease public health relevance receptor translational study

项目摘要

DESCRIPTION (provided by applicant): Epidemiological evidence demonstrates that obesity is rising exponentially to pandemic levels in the USA. The failure of current pharmacological approaches to treat obesity strongly indicates that new therapeutic strategies are required. New strategies require new knowledge. We recently identified a peptide named TLQP-21 which is encoded by the VGF gene. TLQP-21 binds the G-protein coupled receptor Complement 3a receptor1 (C3aR1), potentiates ¿-adrenergic receptors (¿AR)-induced lipolysis and, reduces fat mass in obese mice. TLQP-21 also improves diabetes and has a very safe cardiovascular profile. Much remains to be established on it molecular mechanism of action. Similarly, the role of C3aR1 is well established in immunity but its functional role in adipocytes and obesity is poorly understood. We propose a project in which the Central Hypothesis will be tested that TLQP-21 opposes obesity by enhancing lipolysis with a mechanism requiring priming by cAMP and mediated by increased intracellular calcium concentration. The Specific Aim (SA)1 will determine the role of cAMP on priming TLQP-21-induced activation of C3aR1 in adipocytes and the role of increased [Ca2+]i on its pro-lipolytic effect. The SA2 will investigate the physiologicl consequence of introducing an inactive TLQP-21 mutant on the development of obesity in mice and the behavior of the peptide in a C3aR1 ko mouse. Finally, SA3 will focus on the pro-lipolytic effect of TLQP-21 in human adipocytes. The impact of successful achievement of the aims of this project will be significant on the field. After the failure of sympathomimetic drugs and other pro-lipolytic agents to cure obesity, current therapeutic approaches primarily target feeding or nutrient absorption through the gastro-enteric tract. These more recent approaches are not devoid of adverse effects. The mechanism of action of TLQP-21 has the potential to cure obesity by selectively and safely reducing the excessive adipose fat mass.

描述（由适用提供）：流行病学证据表明，肥胖症正在指数上升到美国的大流行水平。当前的药理学方法治疗肥胖症的失败表明需要新的治疗策略。新策略需要新的知识。我们最近确定了一个名为TLQP-21的肽，该肽由VGF基因编码。 TLQP-21结合G蛋白偶联受体补体3A受体1（C3AR1），势型 - 肾上腺肾上腺肾上腺素（€）诱导的脂肪分解，并减少肥胖小鼠的脂肪质量。 TLQP-21还可以改善糖尿病，并具有非常安全的心血管剖面。在IT分子作用机理上仍有许多待确定。同样，C3AR1的作用在免疫力方面已经很好地确定，但其在脂肪细胞和肥胖症中的功能作用鲜为人知。我们提出了一个项目，其中将测试中央假设，即TLQP-21通过通过cAMP启动并通过增加细胞内钙浓度介导的机制来增强脂解，从而反对肥胖。具体目的（SA）1将确定cAMP在脂肪细胞中启动TLQP-21诱导的C3AR1激活以及[Ca2+] I在其促脂溶液中的作用的作用。 SA2将研究引入无活性TLQP-21突变体对小鼠肥胖的发展以及在C3AR1 KO小鼠中的行为的结果。最后，SA3将集中于人类脂肪细胞中TLQP-21的促脂效应。成功实现该项目目标的影响将在该领域具有重要意义。交感神经药物和其他人失败后促脂溶剂可治愈肥胖，当前的治疗方法主要靶向喂养或通过胃肠道靶向吸收。这些最新的方法并非没有不利影响。 TLQP-21的作用机理有可能通过选择性和安全地减少过量的脂肪脂肪量来治愈肥胖。