LOUSIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。肥胖与患2型糖尿病(DM2)的风险增加有关。通过解偶联蛋白(UCP1)介导的产热调节体重可能是减少人类肥胖的有效机制，原因如下：(1)产热与能量平衡密切相关；(2)产热受到交感神经系统通过肾上腺素能信号的严格调控，并为开发特定的激动剂提供了机会。然而，由于成人拥有少量明确的棕色脂肪组织(BAT)，识别白色脂肪组织(WAT)中诱导棕色脂肪细胞的分子机制非常重要。关于白色脂肪组织中脂肪细胞分化和棕色脂肪细胞诱导的新信息有望克服这一问题。事实上，几项使用转基因小鼠的研究表明，在WAT中诱导棕色脂肪细胞(IBA)可以减少饮食诱导的肥胖，并防止胰岛素抵抗。成人WAT中产热棕色脂肪细胞的转化依赖于肾上腺素能刺激的cAMP依赖的信号通路。CAMP对基因转录的调节至少由三个因子介导，这些因子与靶基因调节区中的Cre基序结合。CREB是转录激活剂，ICER和大多数CREM异构体都是阻遏物。我们观察到这些因子在肩峰间蝙蝠发育和冷适应过程中的表达水平和磷酸化模式的变化，以及在转化为棕色脂肪的过程中的变化。(阐明cAMP信号在棕色脂肪细胞发育和生理反应中的重要性，了解这些异构体如何在转录和转录后水平上进行调控，将为预防人类肥胖提供新的策略。这项建议试图确定：(I)刺激IBA的特定CREB亚型；(Ii)CREM基因失活对IBA和胰岛素敏感性的影响；以及(Iii)CREM基因在脂肪组织中的转录调控。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity is linked with increased risk for developing type 2 diabetes (DM2). Regulation of body weight through uncoupling protein (UCP1) mediated thermogenesis could be an effective mechanism to reduce human obesity for several reasons; (i) thermogenesis is closely related to energy balance, (ii) thermogenesis is tightly regulated by the sympathetic nervous system through adrenergic signaling and provides opportunities to develop a specific agonist. However, as adult humans possess little amount of defined brown adipose tissue (BAT), it is important to identify the molecular mechanisms to induce brown adipocytes in white adipose tissues (WAT). Emerging information on fat cell differentiation and brown adipocyte induction in white adipose tissue promises to overcome this problem. Indeed, several studies using genetically modified mice have shown that induction of brown adipocytes (IBA) in WAT reduces diet-induced obesity and prevents insulin resistance. The conversion of thermogenic brown adipocytes in WAT of adults is dependent upon adrenergic stimulation of a cAMP-dependent signaling pathway. The regulation of gene transcription by cAMP is mediated by at least three factors that bind to the CRE motif found in the regulatory regions of target genes. CREB is an activator of transcription, ICER and most of CREM isoforms are repressors. We have observed changes in expression levels and the patterns of phosphorylation of the isoforms for these factors during interscapular BAT development and cold adaptation, and in WAT during conversion to brown fat. (liven the importance of cAMP signaling in the development and physiological response of brown adipocytes, understandings how these isoforms are regulated at the transcriptional and post-transcriptional levels will provide new strategies to prevent obesity in human. This proposal seeks to identify; (i) specific CREB isoform that stimulate IBA; (ii) the effects of a CREM gene inactivation on IBA and insulin sensitivity, and (iii) transcriptional regulation of the CREM gene in adipose tissue.