RBP4调控猪前体脂肪细胞分化的机制研究
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摘要
脂肪细胞的分化是极其复杂的生物学过程,在受到一系列转录因子级联调控的同时,各种细胞因子也能够通过复杂的信号转导,参与启动和调控脂肪细胞的分化和维持细胞特性。作为机体重要的内分泌器官之一,脂肪组织分泌的脂肪细胞因子对脂肪细胞的形成发挥着关键的调控作用。经研究证实,脂肪细胞因子的功能性紊乱会导致肥胖和胰岛素抵抗(Insulin Resistance, IR)等相关代谢疾病。除此之外,脂肪细胞因子还能参与调节家畜体脂沉积和肌肉发育等肉质性状。因此,深入研究脂肪细胞因子作用的分子机理,已成为阐明脂肪组织形成的重要组成部分,并对畜牧业生产的肉质改良有着重要意义。
RBP4属于脂质运载蛋白家族成员,是视黄醇(维生素A)的特定转运蛋白。RBP4将肝脏储存的视黄醇转运到其他外周组织,并协助视黄醇发挥生理功能。研究发现RBP4作为脂肪细胞因子,能够参与调控脂肪细胞的葡萄糖吸收,并在机体IR中发挥重要作用。RBP4的新功能推动了病理与生理机制、脂肪细胞因子与炎症反应之间关系的探讨,使其成为药物开发的新靶标。但目前有关RBP4对脂肪细胞分化的机理研究相对较少。
动物脂肪沉积与肌肉发育实验室前期研究发现,RBP4在同一品种猪的不同发育阶段的脂肪组织中表达差异显著,推测其可能在脂肪细胞分化过程中发挥重要作用。因此,为验证RBP4的细胞学功能,首先检测了RBP4在猪前体脂肪细胞分化过程中的时序表达；然后通过构建RBP4表达载体和干扰载体,外源增加或减少猪前体脂肪细胞中RBP4的表达量,采用油红O染色、real-time qPCR和Western blot等细胞分子生物学技术,从形态学和基因表达水平检测RBP4对猪前体脂肪细胞成脂分化的影响,为深入研究其在脂肪细胞分化过程中的作用机制奠定基础。此外,结合insulin刺激和insulin信号通路特异性抑制剂(LY294002)处理,进一步明确RBP4与insulin信号通路之间的互作方式及具体作用位点,为阐明RBP4参与调控insulin信号通路的作用机理提供参考依据。最后,通过对小鼠注射RBP4腺病毒,运用冰冻切片、免疫荧光和Western blot等研究技术,检测其对小鼠腹部脂肪组织的影响,对体外细胞实验进行补充和完善。
获得了以下主要研究结果：
1.在猪脂肪细胞形成过程中,RBP4随着脂质的积累表达升高,并且高表达于成熟脂肪细胞,主要存在于脂肪细胞的胞质中。
2.构建猪RBP4基因腺病毒表达载体,并获得重组腺病毒Ad-RBP4,滴度可达到8.6×109pfu/ml,能够稳定增加猪前体脂肪细胞中RBP4的表达量。在此基础上,初步揭示了RBP4对猪前体脂肪细胞分化的抑制作用,主要体现在其降低了成脂关键基因的表达,同时增加了脂解基因ATGL和HSL的mRNA水平。
3.构建猪RBP4基因慢病毒干扰载体,并获得重组慢病毒,滴度达到6.5×107pfu/ml。感染细胞后,能有效降低猪前体脂肪细胞内源性RBP4基因的表达(干扰效率在60%以上)。干扰RBP4能增加细胞内脂质积累,增加成脂基因表达,促进猪前体脂肪细胞分化。
4.RBP4主要通过作用于AKT参与调节insulin信号通路,发挥其抑制成脂的作用。此外,在干扰RBP4的情况下,能够在一定程度上缓解胰岛素信号通路特异性抑制剂LY294002的抑制作用。在成熟脂肪细胞中,RBP4能够与AKT形成复合物。
5.对小鼠进行腹腔注射Ad-RBP4,可以实现RBP4的异位表达。与对照组相比,RBP4可以减低小鼠腹脂的沉积速度,使其细胞直径下降。同时,RBP4能够通过抑制AKT的磷酸化,引起小鼠腹脂的胰岛素抵抗。
本研究以猪前体脂肪细胞为实验材料,从正反两方面证实RBP4是脂肪细胞成脂分化的负调控因子。并结合体内体外的研究结果,验证了RBP4在脂肪细胞中造成胰岛素抵抗的机制足由于抑制了AKT的磷酸化,从而阻断了insulin信号通路。
Adipogenesis is now considered to be a dynamic and plastic process, and involves the coordination of a tightly regulated transcriptional program via numerous paracrine and endocrine factors, which regulate the differentiation of adipocytes and maintain the phenotype of mature adipocytes. It is now well recognized that adipose tissue is one of endocrinal organs and secretes various adipokines, which are likely to represent major contributions to adipose tissue biology. This dysregulation of adipose-secreted factors may promote insulin resistance and obesity-linked metabolic disorders. Moreover, adipokines also effect the fat accumulation and muscle development in livestock. So, it is critically important to more fully understand the molecular mechanisms of adipokines in the adipogenesis and meat quality improvement in animal husbandry.
Retinol-binding protein4(RBP4), one of the members of the lipocalin superfamily, is a specific transport protein for retinoid (vitamin A). RBP4is responsible to transport retinoid from liver to extrahepatic tissues and assists in retinoid metabolism and actions. Until2005, it has been reported that RBP4is a novel adipocyte-secreted hormone that regulates the glucose absorption in adipocytes and provokes insulin resistant states associated with obesity. The new function of RBP4promotes to explore the relation between pathological and physiological mechanism, adipokines and inflammatory response. Therefore, it is possible that RBP4will be a new therapeutic target. However, the mechanisms underlying RBP4affects preadipocyte differentiation are still not well understood.
Previous studies have shown that RBP4expression is significant difference in the adipose tissue of different developmental stages in the same porcine breed, with a putative important role in the differentiation of adipocytes. To investigate the RBP4biological function, its expression was firstly examined in the adipogenesis. Then RBP4expression and interference vector were constructed to increase or decrease its level in porcine preadipocytes. The changes in morphology and gene expression levels were examined by Oil Red O staining, real-time qPCR and Western blot analysis to evaluate the effect of RBP4on the differentiation of porcine preadipocytes. Next, insulin-induced and the specific inhibitor of insulin signaling (LY294002) was used to clarify the interaction between RBP4and insulin signaling. Finally, frozen section, immunofluorescence and Western blot were adopted to detect Ad-RBP4affects abdominal fat tissue in mice, which provide more evidence for experiment in vitro.
The specific results are as follows:
1. The expression of RBP4was increased in the porcine adipogenesis. RBP4was highly expressed in adipoctyes compared to preadipocytes and was predominantly localized in the cytoplasm of preadipocytes and adipocytes.
2. RBP4recombinant adenovirus vector was constructed correctly, virus titer was8.6×109pfu/ml. RBP4expression was remarkably increased in porcine preadipocytes in Ad-RBP4. The results showed that adipogenic differentiation of porcine preadipocytes was inhibited by the overexpression of RBP4. It reflected that mRNA and protein expression levels of adipocyte marker genes were decreased and mRNA of lipolysis genes were enhanced.
3. Porcine RBP4lentivirus interfering vector was constructed. Virus titer was6.5×107pfu/ml, then infected the porcine preadipocytes, RBP4mRNA and protein expression was remarkably reduced by approximate60%in porcine preadipocytes. The data confirmed that preadipocytes differentiation was promoted and the expression levels of PPARy, SREBP-lc and aP2were increased in adipocytes by knockdown of RBP4.
4. RBP4had a suppressive effect as well on the differentiation of porcine preadipocytes by decreasing the activation of insulin signaling pathway. However, the activation of insulin signaling mediated by the knockdown of RBP4in porcine preadipocytes was recovered in the suppression of LY294002. RBP4interacted physically with AKT in mature porcine adipocytes. Taken together, RBP4mainly changed the activity of AKT, which involved in regulating the insulin signaling.
5. Ad-RBP4was injected in mice in order to promote RBP4ectopic expression. Compared with control, the rate of abdominal fat deposition was slower and their adipocytes size was smaller in Ad-RBP4injection group. Besides, RBP4could induce the insulin resistance in abdominal fat tissue.
The work presented in this thesis establishes RBP4as a potent negative regulator of adipogenesis of porcine adipocytes. In addition, the underlying cellular mechanism of RBP4induces insulin resistance in adipocytes is that RBP4inhibits the phosphorylation of AK.T at threonine (308) and blocks the insulin signaling pathway.
RBP4属于脂质运载蛋白家族成员,是视黄醇(维生素A)的特定转运蛋白。RBP4将肝脏储存的视黄醇转运到其他外周组织,并协助视黄醇发挥生理功能。研究发现RBP4作为脂肪细胞因子,能够参与调控脂肪细胞的葡萄糖吸收,并在机体IR中发挥重要作用。RBP4的新功能推动了病理与生理机制、脂肪细胞因子与炎症反应之间关系的探讨,使其成为药物开发的新靶标。但目前有关RBP4对脂肪细胞分化的机理研究相对较少。
动物脂肪沉积与肌肉发育实验室前期研究发现,RBP4在同一品种猪的不同发育阶段的脂肪组织中表达差异显著,推测其可能在脂肪细胞分化过程中发挥重要作用。因此,为验证RBP4的细胞学功能,首先检测了RBP4在猪前体脂肪细胞分化过程中的时序表达；然后通过构建RBP4表达载体和干扰载体,外源增加或减少猪前体脂肪细胞中RBP4的表达量,采用油红O染色、real-time qPCR和Western blot等细胞分子生物学技术,从形态学和基因表达水平检测RBP4对猪前体脂肪细胞成脂分化的影响,为深入研究其在脂肪细胞分化过程中的作用机制奠定基础。此外,结合insulin刺激和insulin信号通路特异性抑制剂(LY294002)处理,进一步明确RBP4与insulin信号通路之间的互作方式及具体作用位点,为阐明RBP4参与调控insulin信号通路的作用机理提供参考依据。最后,通过对小鼠注射RBP4腺病毒,运用冰冻切片、免疫荧光和Western blot等研究技术,检测其对小鼠腹部脂肪组织的影响,对体外细胞实验进行补充和完善。
获得了以下主要研究结果：
1.在猪脂肪细胞形成过程中,RBP4随着脂质的积累表达升高,并且高表达于成熟脂肪细胞,主要存在于脂肪细胞的胞质中。
2.构建猪RBP4基因腺病毒表达载体,并获得重组腺病毒Ad-RBP4,滴度可达到8.6×109pfu/ml,能够稳定增加猪前体脂肪细胞中RBP4的表达量。在此基础上,初步揭示了RBP4对猪前体脂肪细胞分化的抑制作用,主要体现在其降低了成脂关键基因的表达,同时增加了脂解基因ATGL和HSL的mRNA水平。
3.构建猪RBP4基因慢病毒干扰载体,并获得重组慢病毒,滴度达到6.5×107pfu/ml。感染细胞后,能有效降低猪前体脂肪细胞内源性RBP4基因的表达(干扰效率在60%以上)。干扰RBP4能增加细胞内脂质积累,增加成脂基因表达,促进猪前体脂肪细胞分化。
4.RBP4主要通过作用于AKT参与调节insulin信号通路,发挥其抑制成脂的作用。此外,在干扰RBP4的情况下,能够在一定程度上缓解胰岛素信号通路特异性抑制剂LY294002的抑制作用。在成熟脂肪细胞中,RBP4能够与AKT形成复合物。
5.对小鼠进行腹腔注射Ad-RBP4,可以实现RBP4的异位表达。与对照组相比,RBP4可以减低小鼠腹脂的沉积速度,使其细胞直径下降。同时,RBP4能够通过抑制AKT的磷酸化,引起小鼠腹脂的胰岛素抵抗。
本研究以猪前体脂肪细胞为实验材料,从正反两方面证实RBP4是脂肪细胞成脂分化的负调控因子。并结合体内体外的研究结果,验证了RBP4在脂肪细胞中造成胰岛素抵抗的机制足由于抑制了AKT的磷酸化,从而阻断了insulin信号通路。
Adipogenesis is now considered to be a dynamic and plastic process, and involves the coordination of a tightly regulated transcriptional program via numerous paracrine and endocrine factors, which regulate the differentiation of adipocytes and maintain the phenotype of mature adipocytes. It is now well recognized that adipose tissue is one of endocrinal organs and secretes various adipokines, which are likely to represent major contributions to adipose tissue biology. This dysregulation of adipose-secreted factors may promote insulin resistance and obesity-linked metabolic disorders. Moreover, adipokines also effect the fat accumulation and muscle development in livestock. So, it is critically important to more fully understand the molecular mechanisms of adipokines in the adipogenesis and meat quality improvement in animal husbandry.
Retinol-binding protein4(RBP4), one of the members of the lipocalin superfamily, is a specific transport protein for retinoid (vitamin A). RBP4is responsible to transport retinoid from liver to extrahepatic tissues and assists in retinoid metabolism and actions. Until2005, it has been reported that RBP4is a novel adipocyte-secreted hormone that regulates the glucose absorption in adipocytes and provokes insulin resistant states associated with obesity. The new function of RBP4promotes to explore the relation between pathological and physiological mechanism, adipokines and inflammatory response. Therefore, it is possible that RBP4will be a new therapeutic target. However, the mechanisms underlying RBP4affects preadipocyte differentiation are still not well understood.
Previous studies have shown that RBP4expression is significant difference in the adipose tissue of different developmental stages in the same porcine breed, with a putative important role in the differentiation of adipocytes. To investigate the RBP4biological function, its expression was firstly examined in the adipogenesis. Then RBP4expression and interference vector were constructed to increase or decrease its level in porcine preadipocytes. The changes in morphology and gene expression levels were examined by Oil Red O staining, real-time qPCR and Western blot analysis to evaluate the effect of RBP4on the differentiation of porcine preadipocytes. Next, insulin-induced and the specific inhibitor of insulin signaling (LY294002) was used to clarify the interaction between RBP4and insulin signaling. Finally, frozen section, immunofluorescence and Western blot were adopted to detect Ad-RBP4affects abdominal fat tissue in mice, which provide more evidence for experiment in vitro.
The specific results are as follows:
1. The expression of RBP4was increased in the porcine adipogenesis. RBP4was highly expressed in adipoctyes compared to preadipocytes and was predominantly localized in the cytoplasm of preadipocytes and adipocytes.
2. RBP4recombinant adenovirus vector was constructed correctly, virus titer was8.6×109pfu/ml. RBP4expression was remarkably increased in porcine preadipocytes in Ad-RBP4. The results showed that adipogenic differentiation of porcine preadipocytes was inhibited by the overexpression of RBP4. It reflected that mRNA and protein expression levels of adipocyte marker genes were decreased and mRNA of lipolysis genes were enhanced.
3. Porcine RBP4lentivirus interfering vector was constructed. Virus titer was6.5×107pfu/ml, then infected the porcine preadipocytes, RBP4mRNA and protein expression was remarkably reduced by approximate60%in porcine preadipocytes. The data confirmed that preadipocytes differentiation was promoted and the expression levels of PPARy, SREBP-lc and aP2were increased in adipocytes by knockdown of RBP4.
4. RBP4had a suppressive effect as well on the differentiation of porcine preadipocytes by decreasing the activation of insulin signaling pathway. However, the activation of insulin signaling mediated by the knockdown of RBP4in porcine preadipocytes was recovered in the suppression of LY294002. RBP4interacted physically with AKT in mature porcine adipocytes. Taken together, RBP4mainly changed the activity of AKT, which involved in regulating the insulin signaling.
5. Ad-RBP4was injected in mice in order to promote RBP4ectopic expression. Compared with control, the rate of abdominal fat deposition was slower and their adipocytes size was smaller in Ad-RBP4injection group. Besides, RBP4could induce the insulin resistance in abdominal fat tissue.
The work presented in this thesis establishes RBP4as a potent negative regulator of adipogenesis of porcine adipocytes. In addition, the underlying cellular mechanism of RBP4induces insulin resistance in adipocytes is that RBP4inhibits the phosphorylation of AK.T at threonine (308) and blocks the insulin signaling pathway.
引文
陈健.2004.RBP4作为核受体辅活化子新功能的研究.[博士学位论文].重庆：第三军医大学
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