BROWN FAT THERMOGENESIS RESPONSE TO COLD AND AGE

描述：（改编自申请人摘要） 本项目的目标是调查 衰老大鼠棕色脂肪组织（BAT）产热。 BAT中的非颤抖性产热是一个重要的热量来源， 动物暴露在寒冷中后，尤指适应寒冷的动物 大鼠 这项建议有四个具体目标。 (1)以确定 如果冷诱导的BAT解偶联蛋白（UCP）基因表达是 由β-3-肾上腺素能受体（β-3AR）以外的受体介导， 衰老的老鼠 最佳可得技术中的β-AR群体主要包括 非典型β-3AR亚型和该受体介导诱导 的BAT UCP。然而，冷诱导的产热是 在衰老大鼠中比β-3AR保存的程度更大 刺激产热，表明另一种途径可能是介导 老年大鼠的产热作用 第一个目标是检查和 比较冷刺激和β-3-激动剂刺激的时间过程 通过评估UCP mRNA和UCP水平来评估UCP的基因表达 通过6个月、12个月和24个月大鼠的免疫反应性。 (2)以确定 如果产热是由β-1AR或α-1-肾上腺素能介导的， 受体（α-1 AR）而不是β-3 AR。 的 申请人的数据表明，α-1AR对于 与年轻大鼠相比，老年大鼠的产热反应。 第二个目标 将检查和比较产热（O2消耗和 线粒体GDP结合），UCP基因表达和 用内源性激动剂去甲肾上腺素刺激后的UCP (NE)β-3-激动剂，CGP-1277 A; α-1-激动剂，phenylethyl; β-1选择性激动剂，他唑洛尔;以及后受体药物 如毛喉素和cAMP类似物Sp-cAMPS。 (3)确定β受体激动剂是否使β-3 AR脱敏。 它有 有人认为，β-3 AR可能不会被儿茶酚胺脱敏 与β-1或β-2 AR的作用方式相同。 申请人建议 评估β-3和β-1信号转导的脱敏作用， 评估受体数量、腺苷酸环化酶活性和基因 通过评估β 3和β 1 mRNA表达β 3和β 1 AR 大鼠给予NE、CGP-12177 A和他唑洛尔后BAT中 三个年龄。 (4)以确定是否冷适应或慢性药物 治疗可以恢复BAT对β-3-激动剂的产热反应， 老鼠会 UCP的合成（因此， 产热）可以通过药物（β-激动剂）增加，或 冷暴露（Cold Exposure） 此外，有数据显示， β-激动剂治疗可以上调β-3AR。 第四个目标 这项建议是恢复减少β-3AR介导的产热， 通过冷适应或长期给予 CGP-12177 A和/或苯乙醯胺。产热（体温和 耗氧量）与UCP基因相关 表达、GDP结合和β-AR信号转导， 两个年龄段的慢性药物治疗和冷适应大鼠。

DESCRIPTION: (Adapted from the applicant's abstract) The goal of this project is to investigate the impairment of thermogenesis in brown adipose tissue (BAT) in the senescent rat. Nonshivering thermogenesis in BAT is an important source of heat to warm an animal after exposure to the cold, especially in the cold-adapted rat. There are four specific aims to this proposal. (1) To determine if the cold-induced gene expression of BAT uncoupling protein (UCP) is mediated by other than beta-3-adrenergic receptors (beta-3ARs) in senescent rats. The population of beta-ARs in BAT consists mostly of the atypical beta-3AR subtype and this receptor mediates the induction of BAT UCP in young rats.However, cold-induced thermogenesis is preserved in senescent rats to a greater extent than is beta-3AR stimulated thermogenesis, suggesting another pathway may be mediating thermogenesis in older rats. The first goal will be to examine and compare the time-course of cold-stimulated and beta-3-agonist-stimulated gene expression of UCP by assessment of UCP mRNA and the level of UCP by immunoreactivity in rats of 6-, 12- and 24-months. (2) To determine if thermogenesis is mediated by beta-1ARs or alpha-1-adrenergic receptors (alpha-1 ARs) rather than beta-3ARs in senescent rats. The applicants' data indicate that alpha-1 ARs are more important for the thermogenic response in old compared to young rats. The second goal will be to examine and compare thermogenesis (O2 consumption and mitochondrial GDP binding), the gene expression of UCP and the level of UCP following stimulation with the endogenous agonist, norepinephrine (NE); the beta-3-agonist, CGP-1277A; the alpha-1-agonist, phenylephrine; the beta-1 selective agonist, tazolol; as well as post receptor agents such as forskolin and the cAMP analog, Sp-cAMPS in rats of three ages. (3) To determine if beta-3ARs are desensitized by beta-agonists. It has been suggested that beta- 3ARs may not be desensitized by catecholamines in the same manner as beta-1 or beta-2ARs. The applicants propose to assess desensitization of beta-3 and beta-1 signal transduction by assessing receptor number, adenylate cyclase activity, and the gene expression of beta-3 and beta-1ARs by assessing beta-3 and beta-1 mRNA in BAT following NE, CGP-12177A and tazolol administration in rats of three ages. (4) To determine if cold adaptation or chronic drug treatment can restore the BAT thermogenic response to beta-3-agonists in aged rats. The synthesis of UCP (and therefore the capacity for thermogenesis) can be increased by drugs (beta-agonists) or physiologically (cold exposure). In addition, some data suggest that beta-agonist treatment can up regulate beta- 3ARs. The fourth goal of this proposal is to restore the reduced beta- 3AR-mediated thermogenic response with age by cold adaptation or chronic administration of CGP-12177A and/or phenylephrine. Thermogenesis (body temperature and oxygen consumption) will be examined and correlated with UCP gene expression, GDP binding, and beta-AR signal transduction in control and chronically drug-treated and cold-adapted rats of two ages.