GENETIC ANALYSIS OF B3 ADRENERGIC RECEPTOR FUNCTION

肥胖是一种普遍的疾病，通常会导致糖尿病， 心血管疾病 我们最近发现转基因小鼠 设计使棕色脂肪缺乏变得明显肥胖，这表明 棕色脂肪可以防止肥胖的发展。 我们现在寻求 为了更好地理解棕色脂肪的调节机制， 特别是β/3-肾上腺素能受体（β/3-AR）的作用。 棕色脂肪的活动主要由交感神经系统控制。 神经系统 去甲肾上腺素，从交感神经释放出来， 通过与肾上腺素受体结合激活棕色脂肪。 最近，布朗 已经发现脂肪具有高度特异性的β-肾上腺素能 受体（β-AR），称为β/3-AR。 这种受体是最 在脂肪组织中有丰富的β-AR，在遗传上减少了70-98%， 肥胖的模型。 药企纷纷合成“非典型” 刺激β/3-AR的β-AR激动剂，并且这些化合物保持 有望成为抗肥胖、抗糖尿病药物。 由于这些原因， 对β/3-AR和刺激它的药物有很大的兴趣。 然而，β/3-AR在正常生理学中的功能， 非典型β-AR激动剂产生作用的机制如下： 不完全理解。 为了解决这些问题，已经对β/3-AR功能进行了遗传分析。 进行。 使用同源重组，我们已经产生了小鼠， 完全缺乏β/3-AR。 这些动物将用于确定 β/3-AR在正常生理学中的功能，并确定受体 非典型的β-AR激动剂通过这些途径产生它们的许多作用。 通过 在选择的缺陷型组织中转基因地重新表达β/3-AR 小鼠，这将是可能的，以建立网站的行动，这些 各种影响。 最后，通过转基因重组β/3-AR， 缺乏人类受体的小鼠，将有可能确定 活化的人β/3-AR增强产热的能力。 给定 这种遗传方法的高度特异性，从 这些小鼠关于这种受体的功能，应该是明确的， 在自然界中。

Obesity is a prevalent disorder that often leads to diabetes and cardiovascular disease. We have recently found that transgenic mice engineered to have brown fat deficiency become markedly obese, suggesting that brown fat protects against the development of obesity. We now seek to better understand the mechanisms by which brown fat is regulated, specifically the role of beta/3-adrenergic receptors (beta/3-ARs). The activity of brown fat is controlled predominantly by the sympathetic nervous system. Norepinephrine, released from sympathetic nerves, activates brown fat by binding to adrenergic receptors. Recently, brown fat has been found to possess a highly specialized beta-adrenergic receptor (beta-AR), termed the beta/3-AR. This receptor is the most abundant beta-AR in adipose tissue and is decreased by 70-98% in genetic models of obesity. Pharmaceutical companies have synthesized "atypical" beta-AR agonists which stimulate beta/3-ARs, and these compounds hold promise as anti-obesity, anti-diabetes agents. For these reasons, there is great interest in the beta/3-AR, and the drugs which stimulate it. However, the function of beta/3-ARs in normal physiology, and the mechanisms by which atypical beta-AR agonists produce their effects, are incompletely understood. To address these issues, a genetic analysis of beta/3-AR function has been undertaken. Using homologous recombination, we have generated mice which completely lack beta/3-ARs. These animals will be used to determine the function of beta/3-ARs in normal physiology and to define the receptor through which atypical beta-AR agonists produce their many effects. By reexpressing beta/3-ARs transgenically in selected tissues of deficient mice, it will be possible to establish the sites of action for these various effects. Finally, by transgenically reconstituting beta/3-AR deficient mice with human receptors, it will be possible to determine the capacity of activated human beta/3-ARs to augment thermogenesis. Given the high specificity of this genetic approach, information obtained from these mice concerning the function of this receptor, should be definitive in nature.