Genetic Dissection ot the Central GLP-1 System

描述（由申请人提供）：人们对安全有效地降低糖尿病受试者血糖的新疗法仍然非常感兴趣。天然存在的调节肽胰高血糖素样肽1（GLP-1）对于潜在的抗糖尿病剂表现出多种期望的作用，并且蛋白酶抗性长效GLP-1类似物目前可用于治疗2型糖尿病。GLP-1也是一种内源性神经肽，在中枢神经系统（CNS）中发挥作用，但尚不清楚。鉴于一种或多种GLP-1类似物用于治疗糖尿病患者的可能性越来越大，了解GLP-1的核心作用对于预测持续GLP-1给药的生物学后果越来越重要。GLP-1的CNS表达主要在孤束尾侧核（NTS）内的细胞亚群中。尾侧NTS亚核接收和处理来自胸部和腹部内脏的内脏感觉信息，并且NTS与各种脑区域（包括下丘脑区域，如调节食欲功能的弓状区）连接。此外，NTS位于邻近室周器官，最后区（AP），并含有有孔毛细血管，可能允许循环肽进入细胞核。因此，NTS（包括GLP-1细胞）处于处理来自各种神经和体液来源的信息的主要位置。了解哪些参与能量平衡的肽调节脑干GLP-1神经元的神经元活性将有助于了解中枢GLP-1调节。我们提出一个模型，预测：1）NTS中的GLP-1神经元共表达瘦素受体（Ob-R），并且瘦素施用诱导这些神经元中SOCS-3和STAT-3的活化，2）瘦素诱导膜去极化和/或增加GLP-1 NTS神经元内的兴奋性突触活性，和3）GLP-1神经元中特异性的瘦素受体的缺失将导致食欲过盛和肥胖。本申请中提供的研究旨在直接测试该模型的不同组件。

DESCRIPTION (provided by applicant): There remains intense interest in new therapies that safely and effectively lower blood glucose in diabetic subjects. The naturally occurring regulatory peptide glucagon-like peptide 1 (GLP-1) exhibits multiple desirable actions for a potential anti-diabetic agent, and protease-resistant long-acting GLP-1 analogs are currently available for the treatment of Type 2 diabetes. GLP-1 is also an endogenous neuropeptide that exerts actions in the central nervous system (CNS) that are less well understood. Given the increasing likelihood that one or more GLP-1 analogues will be used to treat diabetic patients, understanding the central role of GLP-1 is increasingly relevant for predicting the biological consequences of sustained GLP-1 administration. The CNS expression of GLP-1 is primarily in a subpopulation of cells within the caudal nucleus tractus solitaries (NTS). Caudal NTS subnuclei receive and process viscerosensory information from thoracic and abdominal viscera and the NTS is reciprocally connected with various brain areas, including hypothalamic areas such as the arcuate that regulate appetitive functions. Additionally, the NTS is located adjacent to a circumventricular organ, the area postrema (AP), and contains fenestrated capillaries, potentially allowing circulating peptides access to the nucleus. The NTS (including GLP-1 cells) is therefore in a prime position to process information arising from a variety of neural and humoral sources. Understanding which peptides, involved in energy balance, modulate neuronal activity of brainstem GLP-1 neurons will aid in the understanding of central GLP-1 regulation. We propose a model that predicts: 1) GLP-1 neurons in the NTS co-express the leptin receptor (Ob-R), and that leptin administration induces the activation of SOCS-3 and STAT-3 in these neurons, 2) leptin induces a membrane depolarization and/or increases excitatory synaptic activity within GLP-1 NTS neurons, and 3) deletion of leptin receptors specifically in GLP-1 neurons will result in hyperphagia and obesity. The studies offered in this application are designed to directly test the different components of this model.