REGULATION OF BROWN FAT TRANSMEMBRANE SIGNALLING

棕色脂肪组织(BAT)的主要功能是产生 对交感神经系统的刺激作出反应的热量。这个 去甲肾上腺素对腺苷环化酶的刺激是控制的中心 蝙蝠的功能。我们的研究表明，慢性神经刺激 通过改变遗传基因来调节蝙蝠的腺酰环化酶系统 腺酰环化酶系统各组分的表达和活性， 包括受体和GTP结合蛋白。这项工作确立了 BAT作为一种模型系统，用于评估神经系统在 信号转导蛋白的协调调控。 使用药理学和分子生物学相结合的方法，我们已经 发现蝙蝠含有最近发现的Beta3受体，在 此外，似乎含有相关的新型非典型受体。非典型 受体似乎是治疗肥胖症的重要新靶点 与肥胖有关的疾病，包括糖尿病、高血压和 心血管疾病。然而，人们对这种组织知之甚少。 非典型β受体的分布或调节，包括β3 受体。我们已经开发出高度灵敏和特异的检测方法 测量典型和非典型的β受体基因表达，以便这些 现在可以进行研究了。我们的具体目标是： 1)研究神经细胞分子成分的神经调节 腺酰环化酶系统在新生儿蝙蝠中的作用 这些组分的表达改变了腺酰环化酶的活性 围产期。 2)研究β受体与BR之间的功能关系 刺激、G(Sa)基因表达水平和G(Sa)蛋白水平 脂肪细胞的体内和体外分析。 3)克隆典型和非典型贝塔病毒并对其进行药理学鉴定 受体，包括β3受体。 4)识别表达非典型β受体的组织并检查 β受体基因表达的神经和内分泌调节 关注非典型的β受体。

The principal function of brown adipose tissue (BAT) is the generation of heat in response to stimulation by the sympathetic nervous system. The stimulation of adenylyl cyclase by norepinephrine is central to the control of BAT function. Our work has shown that chronic neural stimulation regulates the adenylyl cyclase system in BAT by altering the genetic expression and activity of the components of the adenylyl cyclase system, including receptors and GTP-binding proteins. This work has established BAT as a model system for assessing the role of the nervous system in the coordinated regulation of signal-transducing proteins. Using combined pharmacological and molecular biological approaches, we have found that BAT contains the recently-discovered beta3 receptor and, in addition, appears to contain related novel atypical receptors. Atypical receptors appear to be important new therapeutic targets for obesity and obesity-related diseases, including diabetes, hypertension and cardiovascular disease. However, very little is known about the tissue distribution or regulation of atypical beta receptors, including the beta3 receptor. We have developed highly sensitive and specific assays for measuring typical and atypical beta receptor gene expression so that these studies can now be undertaken. Our specific aims are: 1) To examine the neural regulation of the molecular components of the adenylyl cyclase system in neonatal BAT and to determine how changes in the expression of these components alters adenylyl cyclase activity during the perinatal period. 2) To examine the functional relationship between beta receptor stimulation, G (sa) mRNA levels and G (sa) protein levels in brown adipocytes using in vivo and in vitro analyses. 3) To clone and pharmacologically characterize typical and atypical beta receptors, including the beta3 receptor. 4) To identify tissues that express atypical beta receptors and to examine the neural and endocrine regulation of beta receptor gene expression, with a focus upon atypical beta receptors.