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: 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
• 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

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增长，目前治疗肥胖症的药物方法的失败表明需要新的治疗策略。 TLQP-21 肽由 VGF 基因编码，与 G 蛋白偶联受体补体 3a 受体 1 (C3aR1) 结合，增强 ¿ TLQP-21 诱导的脂肪分解和减少肥胖小鼠的脂肪量也可以改善糖尿病，并且其作用的分子机制还有很多待确定。 C3aR1 在免疫方面已得到充分证实，但其在脂肪细胞和肥胖中的功能作用尚不清楚。我们提出了一个项目，其中将测试 TLQP-21 通过增强来对抗肥胖的中心假设。脂肪分解的机制需要 cAMP 启动并由细胞内钙浓度增加介导。具体目标 (SA)1 将确定 cAMP 在启动脂肪细胞中 TLQP-21 诱导的 C3aR1 激活中的作用以及增加的 [Ca2+]i 的作用。 SA2 将研究引入失活的 TLQP-21 突变体对小鼠肥胖发展和行为的生理影响。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。在拟交感神经药物失败后，该项目的目标的成功实现将产生重大影响。和其他人 TLQP-21 的作用机制有可能通过胃肠道进行喂养或营养吸收。有选择地、安全地减少过多的脂肪量。