脂肪因子Sfrp5与肥胖及其相关代谢紊乱的相关性研究
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摘要
背景和目的：
随着经济发展和人们生活水平的提高,肥胖已成为现代社会中最常见的营养障碍性疾病。肥胖是代谢性疾病如2型糖尿病的易感因素，经常与脂肪组织的低炎症状态相关。脂肪组织作为内分泌器官在这种“炎症”状态中发挥的作用也引起了高度关注(4)。脂肪组织中促炎细胞因子和抗炎细胞因子的分泌失调是造成人体肥胖的重要原因。
分泌型卷曲相关蛋白－5(Sfrp5)是一种新鉴定的抗炎脂肪因子，是分泌卷曲相关蛋白(secreted Frizzled-related protein，SFRP)家族中的一员，它可以抑制慢性炎症状态，最终增加胰岛素敏感性，在肥胖以及糖尿病小鼠模型中表达下调。研究表明这些蛋白的一个共同特征为拥有一个富含半胱氨酸的区域(cysteine-rich domain，CRD)，该区域与Wnt受体Frizzled蛋白的CRD具有高度同源性。因此，SFRP蛋白家族可与Frizzled蛋白受体竞争结合Wnt配体，从而对Wnt通路发挥负调控作用。Sfrp5的抗炎作用是通过与脂肪组织表达的Wnt5a结合，抑制Wnt非经典通路的下游靶点JNK的活化，进而减少炎症因子的分泌，并拮抗胰岛素受体底物-1(IRS-1)丝氨酸307磷酸化而实现(3,6)。脂肪细胞分化与糖及脂肪代谢、胰岛素抵抗、2型糖尿病、高脂血症等有非常密切的关系(7)。
本研究的目的是以3T3-L1前脂肪细胞为研究对象,观察3T3-L1前脂肪细胞诱导分化过程中Sfrp5表达和分泌的变化趋势。并建立胰岛素抵抗细胞模型，检测建模及罗格列酮、二甲双胍药物干预后Sfrp5mRNA表达和蛋白分泌的变化。并探讨非糖尿病个体血清中脂肪因子SFRP5水平与肥胖、胰岛素抵抗的相关性。
方法：
体外培养3T3-L1脂肪前体细胞,应用1-甲基-3-异丁基黄嘌呤(IBMX)、地塞米松、胰岛素诱导其分化,予以1μM地塞米松、100nM胰岛素及10ng/l TNF-a、10μM罗格列酮及1mM二甲双胍干预分化第6天的3T3-L1细胞过夜(24小时)。采用RT-PCR、ELISA技术检测不同分化时间、调节因素下脂肪细胞Sfrp5mRNA表达以及上清中蛋白分泌水平。
将244例受试者按体重指数(BMI)分为对照组(77例，BMI<24kg/m2)和超重及肥胖组(170例，BMI≥24kg/m2)。ELISA法测定血清SFRP5水平。数据分析采用SPSS17.0版本，描述性结果采用均值±标准差，两组间比较采用T检验;两变量相关分析运用Pearson相关;多元逐步线性回归用于调整协变量的影响和检验独立因素。在所有分析结果中P＜0.05被认为有显著统计学意义。
结果：
(1) Sfrp5在3T3-L1前脂肪细胞无表达,随着前脂肪细胞分化成熟,该基因转录、蛋白分泌水平逐渐上调, mRNA转录水平在第9天达到高峰(45±6倍, P <0.001))，上清中蛋白的分泌延迟于mRNA表达，在分化第5-6天可以检测到。
(2)1μM地塞米松、100nM胰岛素及10ng/l TNF-a分别使成熟脂肪细胞的Sfrp5mRNA表达水平减少25%(P<0.01)、43%(P<0.01)、58%(P<0.01)，上清中蛋白分泌水平减少10%(P<0.05)、28%(P<0.01)、40%(P<0.01)、57%(P<0.01)；
(3)10μM罗格列酮、1mM二甲双胍分别使成熟脂肪细胞的Sfrp5mRNA表达量增加25%(P<0.01)、28%(P<0.01)，上清中蛋白分泌量增加20%(P<0.01)、28%(P<0.01)。
(4)在总体受试者中，肥胖组血清中Sfrp5的水平显著低于对照组(4.46±0.72vs4.69±0.64ng/ml，P<0.05)。
(5)血清Sfrp5水平与年龄、BMI、收缩压、舒张压、平均压、尿酸无明显相关性(P>0.05),血清Sfrp5水平与女/男性别比、腰臀比、总胆固醇、甘油三酯、低密度脂蛋白胆固醇、空腹血糖、FINS、HOMA2-%B、HOMA2-IR之间存在显著负相关(r值分别为-0.168，-0.134，-0.132，-0.154，-0.146，-0.161，-0.312，-0.228，-0.281，P<0.05)。血清Sfrp5与高密度脂蛋白胆固醇之间存在显著正相关(r值为0.171，P <0.05)。
(6)经过年龄、性别、BMI、腰臀比校正，Sfrp5仍可作为一个独立的变量与胰岛素抵抗呈显著负相关(β=-0.425，P<0.001)。
结论：
(1) Sfrp5在促进前脂肪细胞的分化过程中可能起着重要作用。
(:2) Sfrp5的表达和分泌的下调与胰岛素抵抗的发生密切相关。
(3)罗格列酮、二甲双胍抑制组织慢性炎症状态、改善胰岛素抵抗部分是通过增加成熟脂肪细胞中Sfrp5的生成和分泌来实现的。
(4)血清Sfrp5水平与HOMA2-IR呈显著负相关，提示这种新的脂肪因子可能在肥胖、胰岛素抵抗的病理生理机制中发挥作用。
Background and objective:
Increased incidences of obesity have unfortunately become concurrent with rapideconomic development and improved living standards in the modern society. Obesity, acommon disease of nutritional disturbance, leads to metabolic diseases such as type2diabetes mellitus(1). Obesity is also related to impairments in the endocrine functions ofadipose tissues, such as low inflammatory conditions(2-4).The main cause of human obesityis the secretion imbalance of pro-and anti-inflammatory cytokines in adipose tissues(5).
Secreted frizzled-related protein (SFRP)-5(Sfrp5), a newly identifiedanti-inflammatory adipokine, can inhibit chronic inflammation and consequently improveinsulin sensitivity. Sfrp5expression is abundant in mouse adipocytes, but is decreased invarious rodent models, such as obesity and type2diabetes(6). Studies show that one of thecommon features of SFRPs is a cysteine-rich domain (CRD), which has a high homologywith the CRD of the wingless-type (Wnt) receptor frizzled protein. Therefore, SFRPs couldcompete with the frizzled protein receptor in combining with the Wnt ligand, and Sfrp5plays a negative regulatory role in the Wnt pathway(7,8). The anti-inflammatory function ofSfrp5is enabled by its combination with Wnt5a expressed in adipose tissues, therebyinhibiting the activation of the downstream target c-Jun N-terminal kinase (JNK) ofnon-canonical Wnt signaling. Consequently, the secretion of pro-inflammatory cytokines islimited, and the insulin receptor substrate-1serine307phosphorylation is antagonized(6,9).Adipocyte differentiation is closely related to glucose and lipid metabolism, insulinresistance (IR), type2diabetes mellitus, hyperlipoidemia, etc(10). Therefore, changes inSfrp5expression and secretion during the dynamic process of adipocyte differentiation needto be evaluated.
The present study aimed to investigate the expression of Sfrp5mRNA and changes inthe protein secretion during the dynamic process of adipocyte differentiation. Another aimwas to examine the influence of pathophysiological conditions related to insulin resistance on the expression and secretion of adipocyte Sfrp5. The regulation of Sfrp5expression byrosiglitazone and metformin was also assessed. To investigate the relationship of serumSfrp5with obesity and insulin resistance in non-diabetic individuals.
Methods:
(1) Cells of3T3-L1pre-adipocytes were cultivated via differentiation induced by1-methyl-3-isobutyl xanthenes, dexamethasone, and insulin.
(2) To interfere with the differentiation of6d-old3T3-L1cells,1μM dexamethasone,100nM insulin,10ng/l TNF-a,10μM rosiglitazone, and1mM metformin were applied for24h.
(3)Reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbentassay were performed to examine the expression and protein secretion level of Sfrp5mRNAadipocytes under different differentiation periods and regulated culture component.
(4) On the basis of body mass index (BMI),244subjects were divided withnon-obese group(77cases,BMI<24kg/m2),obese group(170cases,BMI≥24kg/m2).
(5) Serum Sfrp5was detected by ELISA.
(6) Experimental data were analyzed by SPSS17.0. The differences between groupswere tested using T-tset. The correlation of variables was determined by Pearson’scorrelation and multiple linear regression was used to correct the effects of the covariatesand test independent factors. P <0.05was considered statistically significant for allanalysis.
Result:
(1) Sfrp5was not expressed in3T3-L1pre-adipocytes. With the differentiation andmaturity of pre-adipocytes, the gene transcription level and Sfrp5protein secretiongradually became more highly regulated. mRNA expression peaked on the9th day (about45±6times, P <0.001). Protein secretion in the supernatant had a delayed expressioncompared with that of mRNA, and was observable on the2nd and3rd day of differentiation.
(2) mRNA expression in mature adipocytes decreased by20%(P <0.01),22%(P <0.01), and32%(P <0.01) using1μM dexamethasone,100nM insulin, and10ng/l TNF,respectively. The corresponding values for protein secretion levels in the supernatant were15%(P <0.01),17%(P <0.01), and30%(P <0.01),,respectively.
(3) Sfrp5mRNA expression in mature adipose increased by34%(P <0.01) and19% (P <0.01) using10μM rosiglitazone and1mM metformin, respectively. The correspondingvalues for protein secretion quantity in the supernatant increased by10%(P <0.01) and6%(P <0.05), respectively.
(4) In investigated subjects, serum Sfrp5levels were lower in obese group than innon-obese group.
(5)Serum Sfrp5levels did not exhibit evident correlation with age,BMI, systolic bloodpressure, diastolic pressure, mean arterial pressure, uric acid(P>0.05). Serum SFRP5levelswere negatively correlated with gender,waist-hip ratio, total cholesterol, triglycerides, lowdensity lipoprotein cholesterol,fasting plasma glucose, FINS, HOMA2-%B, HOMA2-IR(r=-0.168,-0.134,-0.132,-0.154,-0.146,-0.161,-0.312,-0.228,-0.281,P<0.05). Serum Sfrp5levels were positively correlated with high density lipoprotein cholesterol(r=0.171,P<0.05).
(6)After adjustment for age, gender, BMI, WHR, Serum Sfrp5levels was stillnegatively correlated with HOMA2-IR,(β=-0.425，P<0.001).
Conclusion:
(1) Sfrp5plays an important role in the differentiation of pre-adipocytes.
(2) The dysregulation of Sfrp5expression and secretion directly correlates with insulinresistance.
(3) Rosiglitazone-and metformin-induced resistances to organ inflammation andinsulin sensitivity are improved by enhancing Sfrp5mRNA expression and protein secretionin mature adipocytes.
(4) Serum Sfrp5levels was negatively correlated with HOMA2-IR，which showed thatthis novel adipokine may play a role in the pathophysiology of obesity and insulinresistance.
随着经济发展和人们生活水平的提高,肥胖已成为现代社会中最常见的营养障碍性疾病。肥胖是代谢性疾病如2型糖尿病的易感因素，经常与脂肪组织的低炎症状态相关。脂肪组织作为内分泌器官在这种“炎症”状态中发挥的作用也引起了高度关注(4)。脂肪组织中促炎细胞因子和抗炎细胞因子的分泌失调是造成人体肥胖的重要原因。
分泌型卷曲相关蛋白－5(Sfrp5)是一种新鉴定的抗炎脂肪因子，是分泌卷曲相关蛋白(secreted Frizzled-related protein，SFRP)家族中的一员，它可以抑制慢性炎症状态，最终增加胰岛素敏感性，在肥胖以及糖尿病小鼠模型中表达下调。研究表明这些蛋白的一个共同特征为拥有一个富含半胱氨酸的区域(cysteine-rich domain，CRD)，该区域与Wnt受体Frizzled蛋白的CRD具有高度同源性。因此，SFRP蛋白家族可与Frizzled蛋白受体竞争结合Wnt配体，从而对Wnt通路发挥负调控作用。Sfrp5的抗炎作用是通过与脂肪组织表达的Wnt5a结合，抑制Wnt非经典通路的下游靶点JNK的活化，进而减少炎症因子的分泌，并拮抗胰岛素受体底物-1(IRS-1)丝氨酸307磷酸化而实现(3,6)。脂肪细胞分化与糖及脂肪代谢、胰岛素抵抗、2型糖尿病、高脂血症等有非常密切的关系(7)。
本研究的目的是以3T3-L1前脂肪细胞为研究对象,观察3T3-L1前脂肪细胞诱导分化过程中Sfrp5表达和分泌的变化趋势。并建立胰岛素抵抗细胞模型，检测建模及罗格列酮、二甲双胍药物干预后Sfrp5mRNA表达和蛋白分泌的变化。并探讨非糖尿病个体血清中脂肪因子SFRP5水平与肥胖、胰岛素抵抗的相关性。
方法：
体外培养3T3-L1脂肪前体细胞,应用1-甲基-3-异丁基黄嘌呤(IBMX)、地塞米松、胰岛素诱导其分化,予以1μM地塞米松、100nM胰岛素及10ng/l TNF-a、10μM罗格列酮及1mM二甲双胍干预分化第6天的3T3-L1细胞过夜(24小时)。采用RT-PCR、ELISA技术检测不同分化时间、调节因素下脂肪细胞Sfrp5mRNA表达以及上清中蛋白分泌水平。
将244例受试者按体重指数(BMI)分为对照组(77例，BMI<24kg/m2)和超重及肥胖组(170例，BMI≥24kg/m2)。ELISA法测定血清SFRP5水平。数据分析采用SPSS17.0版本，描述性结果采用均值±标准差，两组间比较采用T检验;两变量相关分析运用Pearson相关;多元逐步线性回归用于调整协变量的影响和检验独立因素。在所有分析结果中P＜0.05被认为有显著统计学意义。
结果：
(1) Sfrp5在3T3-L1前脂肪细胞无表达,随着前脂肪细胞分化成熟,该基因转录、蛋白分泌水平逐渐上调, mRNA转录水平在第9天达到高峰(45±6倍, P <0.001))，上清中蛋白的分泌延迟于mRNA表达，在分化第5-6天可以检测到。
(2)1μM地塞米松、100nM胰岛素及10ng/l TNF-a分别使成熟脂肪细胞的Sfrp5mRNA表达水平减少25%(P<0.01)、43%(P<0.01)、58%(P<0.01)，上清中蛋白分泌水平减少10%(P<0.05)、28%(P<0.01)、40%(P<0.01)、57%(P<0.01)；
(3)10μM罗格列酮、1mM二甲双胍分别使成熟脂肪细胞的Sfrp5mRNA表达量增加25%(P<0.01)、28%(P<0.01)，上清中蛋白分泌量增加20%(P<0.01)、28%(P<0.01)。
(4)在总体受试者中，肥胖组血清中Sfrp5的水平显著低于对照组(4.46±0.72vs4.69±0.64ng/ml，P<0.05)。
(5)血清Sfrp5水平与年龄、BMI、收缩压、舒张压、平均压、尿酸无明显相关性(P>0.05),血清Sfrp5水平与女/男性别比、腰臀比、总胆固醇、甘油三酯、低密度脂蛋白胆固醇、空腹血糖、FINS、HOMA2-%B、HOMA2-IR之间存在显著负相关(r值分别为-0.168，-0.134，-0.132，-0.154，-0.146，-0.161，-0.312，-0.228，-0.281，P<0.05)。血清Sfrp5与高密度脂蛋白胆固醇之间存在显著正相关(r值为0.171，P <0.05)。
(6)经过年龄、性别、BMI、腰臀比校正，Sfrp5仍可作为一个独立的变量与胰岛素抵抗呈显著负相关(β=-0.425，P<0.001)。
结论：
(1) Sfrp5在促进前脂肪细胞的分化过程中可能起着重要作用。
(:2) Sfrp5的表达和分泌的下调与胰岛素抵抗的发生密切相关。
(3)罗格列酮、二甲双胍抑制组织慢性炎症状态、改善胰岛素抵抗部分是通过增加成熟脂肪细胞中Sfrp5的生成和分泌来实现的。
(4)血清Sfrp5水平与HOMA2-IR呈显著负相关，提示这种新的脂肪因子可能在肥胖、胰岛素抵抗的病理生理机制中发挥作用。
Background and objective:
Increased incidences of obesity have unfortunately become concurrent with rapideconomic development and improved living standards in the modern society. Obesity, acommon disease of nutritional disturbance, leads to metabolic diseases such as type2diabetes mellitus(1). Obesity is also related to impairments in the endocrine functions ofadipose tissues, such as low inflammatory conditions(2-4).The main cause of human obesityis the secretion imbalance of pro-and anti-inflammatory cytokines in adipose tissues(5).
Secreted frizzled-related protein (SFRP)-5(Sfrp5), a newly identifiedanti-inflammatory adipokine, can inhibit chronic inflammation and consequently improveinsulin sensitivity. Sfrp5expression is abundant in mouse adipocytes, but is decreased invarious rodent models, such as obesity and type2diabetes(6). Studies show that one of thecommon features of SFRPs is a cysteine-rich domain (CRD), which has a high homologywith the CRD of the wingless-type (Wnt) receptor frizzled protein. Therefore, SFRPs couldcompete with the frizzled protein receptor in combining with the Wnt ligand, and Sfrp5plays a negative regulatory role in the Wnt pathway(7,8). The anti-inflammatory function ofSfrp5is enabled by its combination with Wnt5a expressed in adipose tissues, therebyinhibiting the activation of the downstream target c-Jun N-terminal kinase (JNK) ofnon-canonical Wnt signaling. Consequently, the secretion of pro-inflammatory cytokines islimited, and the insulin receptor substrate-1serine307phosphorylation is antagonized(6,9).Adipocyte differentiation is closely related to glucose and lipid metabolism, insulinresistance (IR), type2diabetes mellitus, hyperlipoidemia, etc(10). Therefore, changes inSfrp5expression and secretion during the dynamic process of adipocyte differentiation needto be evaluated.
The present study aimed to investigate the expression of Sfrp5mRNA and changes inthe protein secretion during the dynamic process of adipocyte differentiation. Another aimwas to examine the influence of pathophysiological conditions related to insulin resistance on the expression and secretion of adipocyte Sfrp5. The regulation of Sfrp5expression byrosiglitazone and metformin was also assessed. To investigate the relationship of serumSfrp5with obesity and insulin resistance in non-diabetic individuals.
Methods:
(1) Cells of3T3-L1pre-adipocytes were cultivated via differentiation induced by1-methyl-3-isobutyl xanthenes, dexamethasone, and insulin.
(2) To interfere with the differentiation of6d-old3T3-L1cells,1μM dexamethasone,100nM insulin,10ng/l TNF-a,10μM rosiglitazone, and1mM metformin were applied for24h.
(3)Reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbentassay were performed to examine the expression and protein secretion level of Sfrp5mRNAadipocytes under different differentiation periods and regulated culture component.
(4) On the basis of body mass index (BMI),244subjects were divided withnon-obese group(77cases,BMI<24kg/m2),obese group(170cases,BMI≥24kg/m2).
(5) Serum Sfrp5was detected by ELISA.
(6) Experimental data were analyzed by SPSS17.0. The differences between groupswere tested using T-tset. The correlation of variables was determined by Pearson’scorrelation and multiple linear regression was used to correct the effects of the covariatesand test independent factors. P <0.05was considered statistically significant for allanalysis.
Result:
(1) Sfrp5was not expressed in3T3-L1pre-adipocytes. With the differentiation andmaturity of pre-adipocytes, the gene transcription level and Sfrp5protein secretiongradually became more highly regulated. mRNA expression peaked on the9th day (about45±6times, P <0.001). Protein secretion in the supernatant had a delayed expressioncompared with that of mRNA, and was observable on the2nd and3rd day of differentiation.
(2) mRNA expression in mature adipocytes decreased by20%(P <0.01),22%(P <0.01), and32%(P <0.01) using1μM dexamethasone,100nM insulin, and10ng/l TNF,respectively. The corresponding values for protein secretion levels in the supernatant were15%(P <0.01),17%(P <0.01), and30%(P <0.01),,respectively.
(3) Sfrp5mRNA expression in mature adipose increased by34%(P <0.01) and19% (P <0.01) using10μM rosiglitazone and1mM metformin, respectively. The correspondingvalues for protein secretion quantity in the supernatant increased by10%(P <0.01) and6%(P <0.05), respectively.
(4) In investigated subjects, serum Sfrp5levels were lower in obese group than innon-obese group.
(5)Serum Sfrp5levels did not exhibit evident correlation with age,BMI, systolic bloodpressure, diastolic pressure, mean arterial pressure, uric acid(P>0.05). Serum SFRP5levelswere negatively correlated with gender,waist-hip ratio, total cholesterol, triglycerides, lowdensity lipoprotein cholesterol,fasting plasma glucose, FINS, HOMA2-%B, HOMA2-IR(r=-0.168,-0.134,-0.132,-0.154,-0.146,-0.161,-0.312,-0.228,-0.281,P<0.05). Serum Sfrp5levels were positively correlated with high density lipoprotein cholesterol(r=0.171,P<0.05).
(6)After adjustment for age, gender, BMI, WHR, Serum Sfrp5levels was stillnegatively correlated with HOMA2-IR,(β=-0.425，P<0.001).
Conclusion:
(1) Sfrp5plays an important role in the differentiation of pre-adipocytes.
(2) The dysregulation of Sfrp5expression and secretion directly correlates with insulinresistance.
(3) Rosiglitazone-and metformin-induced resistances to organ inflammation andinsulin sensitivity are improved by enhancing Sfrp5mRNA expression and protein secretionin mature adipocytes.
(4) Serum Sfrp5levels was negatively correlated with HOMA2-IR，which showed thatthis novel adipokine may play a role in the pathophysiology of obesity and insulinresistance.
引文
1. Hirosumi J, Tuncman G, Chang L, G rgün CZ, Uysal KT, et al., A central role for JNKin obesity and insulin resistance. Nature2002,420(6913):333-6.
2. Miner JL,The adipocyte as an endocrine cell. J Anim Sci,2004,82:935-941
3. Ouchi N, S. Kihara, T. Funahashi, Y. Matsuzawa, K.Walsh, Obesity, adiponectin andvascular inflammatory disease. Curr Opin Lipidol2003,14(6):561-6.
4. Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, et al., Adiponectin protectsagainst myocardial ischemia-reperfusion injury through AMPK-and COX-2–dependentmechanisms.Nat Med.2005,11(10),1096-103.
5. Hotamisligil GS,Shargill NS,Spiegelman BM.Adipose expression of tumor necrosisfactor-alpha:direct role in obesity-linked insulin resistance. Science1993,259:87-91
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