Cbx4在棕色脂肪能量代谢以及Beige细胞形成中的作用

There has been an upsurge of interest in the adipocyte coincident with the onset of the obesity epidemic and the realization that adipose tissue play a major role in the regulation of metabolic function. Brown adipose tissue dissipates chemical energy in the form of heat as a defence against hypothermia and obesity. In addition, certain white fat depots possess a subpopulation of adipocytes called beige or brite cells that can be induced to brown-like adipocytes in response to various stimuli. Both classical brown fat and beige adipocytes are found in adult humans and their mass and /or activity are inversely correlated with body mass index. These findings lead to the proposal that increasing brown fat mass and /or activity or converting white adipocytes to beige adipocytes might be a promising therapeutic strategy for obesity and metabolic diseases..PR domain-containing 16, a zinc finger containing transcription factor, is critical molecular determinant of brown/beige fat cell fate. Fat-specific PRDM16 transgenic mice displayed increased energy expenditure, limit weight gain, and improved glucose tolerance in response to a high-fat diet. However, upstream regulators for PRDM16 in the brown fat largely remain to be identified..Polycomb group (PcG) proteins are major transcriptional repressors that epigenetically modify chromatin. Polycomb proteins form at least two distinct complexes, the Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2), that exert important functions in regulation of cell cycle, DNA repair, cell differentiation, senescence, and death. Besides being a member of PRC1 complex, Cbx4 presents in the same transcriptional complex with PRDM16. Cbx4 preferably expresses in brown adipose tissue and is induced during brown adipogenesis. When co-transfected into 293T cells, Cbx4 increases accumulation of PRDM16 protein probably through its SUMO E3 ligase activity since the SIM1 (SUMO-interacting motif) deletion mutant loses the capability to stabilize PRDM16 protein completely. We predict that Cbx4 may regulate the brown fat gene programs and play roles in white-to-brown adipocytes conversion through stabilization of PRDM16 protein. Here, we are going to perform a series of experiments to explore the functions of Cbx4 in regulation of brown fat energy expenditure and white-to-brown adipocytes conversion and unravel the underlying mechanisms.

棕色脂肪组织和Beige细胞能够将储存在身体内的化学能转换为热量释放出体外，设法增加棕色脂肪组织或Beige细胞的含量或活性成为预防和治疗肥胖的新策略。PRDM16是调节棕色脂肪和Beige细胞形成和功能的至关重要的转录调节因子。做为Polycomb抑制复合体PRC1组成成分之一的Cbx4蛋白，与PRDM16共存于同一个转录复合物中, 并且Cbx4随着棕色脂肪细胞分化其表达水平逐渐增加，在小鼠各组织中也主要表达于棕色脂肪组织，这提示Cbx4可能参与调节棕色脂肪功能。在293T细胞中共表达Cbx4和PRDM16时, PRDM16蛋白水平明显因为Cbx4的存在而增加，Cbx4的这项功能则完全依赖于其蛋白序列中的SIM1结构域。基于以上发现，我们将深入探索Cbx4基因在棕色脂肪能量代谢以及Beige细胞形成过程中的作用，论证Cbx4 做为临床治疗肥胖新靶点的可行性。

脂肪组织是人体重要的代谢器官，在人体内脂肪组织主要存在三种不同的类型，包括白色脂肪组织( White Adipose Tissue, WAT )、棕色脂肪组织( Brown Adipose Tissue, BAT )和米色脂肪组织( Beige Adipose Tissue )。功能活化的棕色和米色脂肪细胞能够直接消耗血液中甘油三酯和葡萄糖，来调节全身能量代谢。因此，产热脂肪细胞功能调节机制成为潜在预防和治疗肥胖的新药靶。在小鼠棕色脂肪组织中高表达的Ifi27(ISG12a)基因的功能目前还未有任何报道。我们的研究发现Ifi27蛋白定位于线粒体中，其表达能够被冷暴露和β3肾上腺素受体激动剂诱导，并且在维持棕色和米色脂肪细胞产热基因表达和三羧酸(TCA)循环、线粒体电子传递(ETC)功能中发挥重要作用。表现为降低Ifi27基因表达时，棕色和米色脂肪细胞的TCA循环关键酶以及电子传递链复合物中部分组分表达都显著降低，同时Ucp1、Cidea等产热基因表达也受到影响，β3肾上腺素受体激活所诱导的白色脂肪棕色化被显著抑制。而在棕色和米色脂肪细胞中过表达Ifi27基因则引起相反的效应。脂肪组织特异性Ifi27基因敲除鼠在棕色脂肪组织产热功能被激活后，其线粒体嵴的数量显著少于野生型小鼠。我们的研究初步揭示了Ifi27通过调节线粒体结构而影响能量代谢和脂肪组织产热功能。