REGULATION OF BROWN FAT TRANSMEMBRANE SIGNALLING

棕色脂肪组织（BAT）的主要功能是产生 由于交感神经系统的刺激而产生的热量。 的 去甲肾上腺素对腺苷酸环化酶的刺激是控制的关键 BAT的功能。 我们的研究表明慢性神经刺激 调节腺苷酸环化酶系统在BAT通过改变遗传 腺苷酸环化酶系统组分的表达和活性， 包括受体和GTP结合蛋白。 这项工作建立了 BAT作为评估神经系统在神经系统疾病中作用的模型系统 信号转导蛋白的协调调节。 通过结合药理学和分子生物学方法，我们 发现BAT含有最近发现的β 3受体， 此外，似乎含有相关的新型非典型受体。 非典型 受体似乎是肥胖症的重要的新治疗靶点， 肥胖相关疾病，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β 3 受体的 我们已经开发出高度敏感和特异性的检测方法， 测量典型和非典型β受体基因表达， 现在可以进行研究。 我们的具体目标是： 1)为了研究神经调节的分子组成部分， 腺苷酸环化酶系统在新生儿BAT，并确定如何变化， 这些组分的表达改变了腺苷酸环化酶在细胞周期中的活性。 围产期 2)为了研究β受体与细胞凋亡之间的功能关系， 刺激、G（sa）mRNA水平和G（sa）蛋白水平 使用体内和体外分析的脂肪细胞。 3)克隆和鉴定典型和非典型β 包括β 3受体。 4)鉴定表达非典型β受体的组织， β受体基因表达的神经和内分泌调节， 重点关注非典型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.