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，达到流行病的水平。目前治疗肥胖的药理学方法的失败强烈表明需要新的治疗策略。新的策略需要新的知识。我们最近发现了一个名为TLQP-21的肽，它是由VGF基因编码的。TLQP-21结合g蛋白偶联受体补体3a受体1 (C3aR1)，增强肾上腺素能受体（AR）诱导的脂肪分解，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功能。它的分子作用机制还有待进一步研究。同样，C3aR1在免疫中的作用已得到证实，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，该项目将检验中心假设，即TLQP-21通过增强脂肪分解来对抗肥胖，其机制需要cAMP启动，并由细胞内钙浓度增加介导。特异性靶（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[Ca2+]i增加对其促脂作用的作用。SA2将研究引入失活TLQP-21突变体对小鼠肥胖发展的生理影响，以及该肽在c3ar1ko小鼠中的行为。最后，SA3将重点关注TLQP-21在人脂肪细胞中的促脂作用。成功实现这个项目的目标将对该领域产生重大影响。失败后使用拟交感神经药物等

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.