This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 istightly 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 whiteadipose 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.
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