Molecular dissection of TLQP-21 peptide functions in obesity

TLQP-21 肽在肥胖中的功能的分子解析

• 批准号: 9115605
• 负责人: Alessandro Bartolomucci
• 金额: $ 32.74万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/9115605
• 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; Disease; Dissection; Engineering; Enteral; Epidemiology; Failure; Fatty acid glycerol esters; Figs - dietary; Forskolin; Future; G-Protein-Coupled Receptors; Genes; Genotype; Health; High Fat Diet; 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; 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; base; energy balance; feeding; improved; mutant; novel; novel strategies; novel therapeutic intervention; nutrient absorption; pandemic disease; receptor; translational study

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(由申请人提供)：流行病学证据表明，肥胖症在美国呈指数级上升到大流行水平。目前治疗肥胖症的药物方法的失败强烈表明需要新的治疗策略。新的战略需要新的知识。我们最近发现了一种名为TLQP-21的多肽，它由VGF基因编码。TLQP-21与G蛋白偶联受体补体3a受体1(C3aR1)结合，增强�肾上腺素能受体(�AR)诱导的脂解作用，减少肥胖小鼠的脂肪量。TLQP-21还可以改善糖尿病，并具有非常安全的心血管特征。关于它的分子作用机制仍有许多有待建立。同样，C3aR1在免疫中的作用已经得到了很好的证实，但它在脂肪细胞和肥胖中的功能作用却鲜为人知。我们提出了一个项目，在这个项目中，将检验中央假设，即TLQP-21通过促进脂肪分解来反对肥胖，其机制需要cAMP启动，并通过增加细胞内钙浓度来调节。具体目标(SA)1将确定cAMP在启动TLQP-21诱导的脂肪细胞C3aR1激活中的作用以及[Ca+]i升高对其促脂质作用的作用。SA2将研究引入失活的TLQP-21突变体对小鼠肥胖发展的生理学后果，以及该肽在C3aR1Ko小鼠中的行为。最后，SA3将重点研究TLQP-21在人类脂肪细胞中的促脂肪分解作用。该项目目标的成功实现将对实地产生重大影响。在交感神经类药物和其他药物失败后 为了治疗肥胖，目前的治疗方法主要针对通过胃肠道的喂养或营养吸收。这些较新的方法并不是没有负面影响。TLQP-21的作用机制可能是通过选择性、安全地减少过量脂肪来治疗肥胖。