Molecular dissection of TLQP-21 peptide functions in obesity

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至流行水平。目前治疗肥胖症的药理学方法的失败强烈表明需要新的治疗策略。新战略需要新知识。我们最近发现了一种名为TLQP-21的肽，它由VGF基因编码。TLQP-21结合G蛋白偶联受体补体3a受体1（C3 aR 1），增强β-肾上腺素能受体（β AR）诱导的脂解作用，并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确定的地方。类似地，C3 aR 1在免疫中的作用已被充分确立，但其在脂肪细胞和肥胖症中的功能作用知之甚少。我们提出了一个项目，在该项目中，中心假设将被测试，TLQP-21通过增强脂解作用，需要启动cAMP和介导的细胞内钙离子浓度增加的机制来对抗肥胖。特异性目的（SA）1将确定cAMP在引发TLQP-21诱导的脂肪细胞中C3 aR 1活化中的作用以及[Ca 2 +]i增加对其促脂解作用的作用。SA 2将研究引入无活性TLQP-21突变体对小鼠肥胖症发展的生理学后果以及肽在C3 aR 1 ko小鼠中的行为。最后，SA 3将关注TLQP-21在人脂肪细胞中的促脂解作用。成功实现该项目的目标将对实地产生重大影响。在拟交感神经药物和其他药物失败后， 虽然促脂解剂用于治疗肥胖症，但目前的治疗方法主要针对通过胃肠道的进食或营养吸收。这些较新的方法并非没有不利影响。TLQP-21的作用机制有可能通过选择性和安全地减少过量的脂肪量来治愈肥胖症。

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.