BROWN FAT THERMOGENESIS RESPONSE TO COLD AND AGE

描述：(改编自申请人的摘要) 该项目的目标是调查 衰老大鼠棕色脂肪组织(BAT)的生热作用。 蝙蝠的非颤抖生热作用是取暖的重要热源 冷暴露后的动物，尤指在适应寒冷的环境中 老鼠。这项提议有四个具体目标。(一)确定 如果冷诱导的BAT解偶联蛋白(UCP)的基因表达 β-3-肾上腺素能受体(β-3ARs)以外的信号转导途径 衰老的老鼠。蝙蝠体内的β-Ars种群主要由 非典型的β-3AR亚型和该受体介导诱导 BAT UCP在幼年大鼠体内的表达。然而，冷诱导的产热是 在衰老大鼠体内的保存程度高于β-3AR 刺激产热，表明另一条途径可能在调节 老年大鼠的生热作用。第一个目标将是检查和 冷刺激与β-3激动剂刺激的时程比较 检测UCP基因表达及UCP水平的研究 通过6个月、12个月和24个月龄大鼠的免疫反应。(二)确定 如果产热是由β-1AR或α-1-肾上腺素能调节的 衰老大鼠的受体(α-1ARs)而不是β-3ARs。这个 申请者的数据表明，阿尔法-1受体对 老年大鼠与年轻大鼠的生热反应。第二个目标 将检查和比较生热作用(氧气消耗和 线粒体GDP结合)、UCP基因表达和 内源性激动剂去甲肾上腺素刺激后的UCP (N)β-3激动剂CGP-1277A、α-1激动剂苯肾上腺素； β-1选择性激动剂他唑洛尔；以及受体后药物 如Forsklin和cAMP类似物，Sp-cAMP在三龄大鼠体内。 (3)确定β-3AR是否被β-激动剂脱敏。它有 已经提出，β-3AR可能不会被儿茶酚胺脱敏 以与β-1或β-2AR相同的方式。申请者建议 评估β-3和β-1信号转导的脱敏 评估受体数量、腺苷环化酶活性和基因 通过检测β-3和β-1mRNA表达β-3和β-1AR 大鼠去甲肾上腺素、CGP-12177A和他唑洛尔对BAT的影响 三个年头。(4)确定感冒适应或慢性药物 治疗可以恢复蝙蝠对β-3激动剂的发热反应 老龄大鼠。UCP的合成(并因此具有 产热作用)可通过药物(β-激动剂)或 生理上(冷暴露)。此外，一些数据表明， β-受体激动剂治疗可以上调β-3ARs。的第四个目标 这项建议是为了恢复减少的β-3AR介导的生热 冷适应或慢性给药对年龄的反应 CGP-12177A和/或苯肾上腺素。生热作用(体温和 耗氧量)将被检测并与UCP基因相关 对照组和对照组的表达、GDP结合和β-AR信号转导 慢性药物治疗和冷适应两个年龄段的大鼠。

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.