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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。肥胖会增加患2型糖尿病（DM2）的风险。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)产热受交感神经系统通过肾上腺素能信号传导严格调节，并为产生特异性激动剂提供了机会。然而，由于成年人拥有少量的棕色脂肪组织（BAT），因此确定在白色脂肪组织（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，一些使用转基因小鼠的研究表明，在WAT中诱导棕色脂肪细胞（IBA）可以减少饮食引起的肥胖，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camp依赖性信号通路的肾上腺素能刺激。cAMP对基因转录的调控是由至少三个与靶基因调控区域中发现的CRE基序结合的因子介导的。CREB是转录的激活因子，而ICER和大多数CREM同工异构体是抑制因子。我们观察到这些因子在肩胛间BAT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过程中的WAT。阐明cAMP信号在棕色脂肪细胞发育和生理反应中的重要性，了解这些同型体是如何在转录和转录后水平上被调节的，将为预防人类肥胖提供新的策略。本建议旨在确定；(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）脂肪组织中CREM基因的转录调控。

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.