内脏脂肪沉积所致肥胖与代谢/心血管疾病关系密切。米色脂肪是主要的产热脂肪，可由白色脂肪前体诱导产生，具有显著的抗肥胖效应； 然与皮下脂肪比，内脏脂肪不易出现“米色化”，其机制未明。PRDM16是调控米色脂肪形成的分子开关，包括全长fPRDM16与sPRDM16 （PR结构域缺失）两种剪切异构体。我们及其他学者发现Sirt1可促进皮下脂肪“米色化”，却不能诱导内脏脂肪“米色化”；我们进一步研究发现Sirt1对皮下与内脏脂肪中fPRDM16及Skip的表达调控存在差异。基于此，本项目拟通过细胞与裸鼠移植实验探讨PR结构域对PRDM16诱导“米色化”的影响及机制是否涉及组蛋白H3K9甲基化，并明确Sirt1/Skip/Ski可否调控内脏脂肪PRDM16选择性剪切而抑制其“米色化”。这有利于揭示内脏脂肪“米色化”的调控机制及基于结构域的小分子药物研发，为内脏型肥胖及相关性疾病防治提供新思路。

Visceral adiposity plays an important role in the development of metabolism and/or cardiovascular diseases. Beige adipose is the major type of thermogenic fat in mouse and human. It derives from myf5-negative white preadipocytes and exerts potential anti-obesity effect. Studies reveal that visceral adipose is more difficult to induce beige remodeling than subcutaneous adipose, but the mechanisms remain unknown. PR-domain protein 16 (PRDM16) has been reported to be the key gene controlling brown/beige adipose formation. It has two major kinds of alternative splicing isoforms: full length PRDM16 (fPRDM16) and short PRDM16 (sPRDM16), and the role of the two isoforms in beige remodeling is not clear. We and other researchers find that Sirt1 inhibits the conversion of visceral white preadipocytes to beige adipose, accompanying with down-regulation of fPRDM16 and up-regulation of Skip and Ski. Therefore, our present study is mainly designed to explore the effects of PR domain in PRDM16-induced beige adipose formation, and to examine whether alternative splicing mediated by Sirt1/Ski/Skip is involved in this process. Such methods as gene transfection, transplantation using nude mice, GST Pull-down, PET-CT are selected. We expect that our study might help to disclose a new regulatory mechanism for visceral beige remodeling, and might bring benefit to the development of small molecular drugs targeting PR domain.