儿童血清FGF21水平与代谢综合征关系的初步研究
摘要
目的：
近年来,由于成纤维细胞生长因子21(FGF21)在动物模型中改善糖脂代谢的良好效果,人们将其作为治疗2型糖尿病的潜在药物寄予厚望。然而,FGF21在人体中的病理生理作用尚不明确,部分研究显示在肥胖、2型糖尿病患者体内FGF21的水平增高,提示存在FGF21抵抗。本研究利用大样本学龄儿童资料,观察血清FGF21水平在儿童的分布及其影响因素,探讨FGF21与儿童期肥胖及代谢综合征(MS)的关系。
方法：
对来自2004年“北京儿童青少年代谢综合征研究”中整群抽样获得的景山学校820名6-18岁学龄儿童,进行体量指标、Tanner分期、空腹血脂谱、空腹血糖、以及血清胰岛素、瘦素、脂联素、抵抗素和FGF21水平测定。FGF21采用双抗体夹心放大酶联免疫法检测；儿童MS采用改良的美国国家胆固醇计划成人治疗小组第3次报告(ATPⅢ)中的定义进行诊断。
结果：
1.血清FGF21水平在两性无显著性差异(P=0.082)。青春发育中期两性FGF21水平均有增加趋势。正常体重、超重和肥胖组儿童FGF21水平逐步升高,但无统计学意义。MS组与非MS组,具有MS组分或不具该组分组FGF21水平无显著性差异。
2.全体对象中,FGF21与腰围、体重指数(BMI)、体脂含量、收缩压(SBP)、舒张压(DBP)、空腹血糖、胰岛素、血脂谱、瘦素、脂联素、抵抗素的双变量分析显示,FGF21仅与舒张压(r=0.08,P=0,023)、瘦素(1=0.085,P=0.015)及抵抗素(r=0.078,P=0.027)具有相关性,调整年龄、性别、BMI后,空腹血糖亦与FGF21显著相关(r=0.074,P=0.038)。
3.将全体儿童按FGF21四分位数分组,可以看到各分组中肥胖儿童比例一致。儿童MS.MS各组分的发生率均表现为FGF21第1分位组较高,第2、第3分位较低,第4分位再度增高的J型曲线。全体对象中MS组分≥1个的比例组间比较具有统计学差异(P=0.016),肥胖儿童中MS发生比例亦具有统计学差异(P=0.044)。女孩中低脂联素血症的发生率随FGF21四分位变化亦表现为上述J型曲线。
4.logistic回归显示,全体儿童中FGF21水平的升高(OR=I.681,P=0.041)或者降低(OR=I.924,P=0.009)均与儿童携带MS组分的风险增加显著相关,肥胖儿童中FGF21的升高与儿童罹患MS风险的增加显著相关(OR=19.971,P=0.013),且这种风险度的增加独立于儿童的年龄、性别和BMI。
结论：
儿童人群中FGF21水平与肥胖无显著相关性。儿童人群中存在FGF21相对缺乏和FGF21抵抗两种状态。过低或过高的FGF21水平均与儿童不良代谢状况相关,提示全体儿童携带MS组分以及肥胖儿童罹患MS风险的增加。
Objective:
Recently, a novel protein, fibroblast growth factor21(FGF21) has gained a lot of attention due to its beneficial effects on glucose homeostasis and lipid metabolism in animal models. However, the physiological and pathologic roles of FGF21in human remain unclear. This study aimed to investigate the relationship between its serum levels and metabolic syndrome (MS) in children.
Methods:
820Chinese subjects aged6to18years were recruited from the Beijing Child and Adolescent Metabolic Syndrome study. Anthropometric parameters, fasting lipid profile, glucose, fasting insulin, leptin, adiponectin, resistin and FGF21were measured. MS was diagnosed according to the modified Adult Treatment Panel Ⅲ (ATPⅢ) criteria.
Results:
There was no sex difference in serum FGF21levels (P=0.082). A slightly increase in FGF21levels during middle puberty was observed in both genders.Though medians of FGF21levels in each group increased progressively from normal weight to overweight to obese, they did not reach statistical significant. FGF21levels in children with and without MS did not show significant difference either.
In the whole cohort, univariate association analysis between FGF21and waist circumference, body mass index (BMI), fat mass percentage, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose, insulin and fasting lipid profile showed that FGF21only had correlation with DBP (r=0.08, P=0.023), leptin (r=0.085, P=0.015) and resistin (r=0.078, P=0.027). Adjusted for age, gender and BMI, fasting blood glucose also correlated with FGF21(r=0.074, P=0.038)
The whole population was then divided into quartiles based on FGF21levels. The percentages of obese children in each group were almost the same. A J-shaped association of the incidences of MS and MS components with FGF21was observed. Both the first and the fouth quartiles were associated with higher incidences of carrying1or more MS components (P=0.016). MS incidences in groups of obese children divided according to the above quartiles also showed significant difference (P=0.044). A J-shaped association of hypoadiponectinemia with FGF21was also observed, but only in girls.
In the whole population, logistic regression analysis showed that both high (OR=1.681,P=0.041) and low(OR=1.924,P=0.009) levels of FGF21were associated with increased risk of carrying metabolic components in children, while in the obese subgroup, high level of FGF21was associated with increased risk of developing MS (OR=19.971, P=0.013),even after ajusting for age, gender and BMI.
Conclusion:
In this study, serum FGF21level did not correlate with obesity. A J-shaped association between FGF21levels and incidences of MS and MS components in children was observed, showing that not only higher level but also lower level of FGF21indicated adverse metabolic profiles.
近年来,由于成纤维细胞生长因子21(FGF21)在动物模型中改善糖脂代谢的良好效果,人们将其作为治疗2型糖尿病的潜在药物寄予厚望。然而,FGF21在人体中的病理生理作用尚不明确,部分研究显示在肥胖、2型糖尿病患者体内FGF21的水平增高,提示存在FGF21抵抗。本研究利用大样本学龄儿童资料,观察血清FGF21水平在儿童的分布及其影响因素,探讨FGF21与儿童期肥胖及代谢综合征(MS)的关系。
方法：
对来自2004年“北京儿童青少年代谢综合征研究”中整群抽样获得的景山学校820名6-18岁学龄儿童,进行体量指标、Tanner分期、空腹血脂谱、空腹血糖、以及血清胰岛素、瘦素、脂联素、抵抗素和FGF21水平测定。FGF21采用双抗体夹心放大酶联免疫法检测；儿童MS采用改良的美国国家胆固醇计划成人治疗小组第3次报告(ATPⅢ)中的定义进行诊断。
结果：
1.血清FGF21水平在两性无显著性差异(P=0.082)。青春发育中期两性FGF21水平均有增加趋势。正常体重、超重和肥胖组儿童FGF21水平逐步升高,但无统计学意义。MS组与非MS组,具有MS组分或不具该组分组FGF21水平无显著性差异。
2.全体对象中,FGF21与腰围、体重指数(BMI)、体脂含量、收缩压(SBP)、舒张压(DBP)、空腹血糖、胰岛素、血脂谱、瘦素、脂联素、抵抗素的双变量分析显示,FGF21仅与舒张压(r=0.08,P=0,023)、瘦素(1=0.085,P=0.015)及抵抗素(r=0.078,P=0.027)具有相关性,调整年龄、性别、BMI后,空腹血糖亦与FGF21显著相关(r=0.074,P=0.038)。
3.将全体儿童按FGF21四分位数分组,可以看到各分组中肥胖儿童比例一致。儿童MS.MS各组分的发生率均表现为FGF21第1分位组较高,第2、第3分位较低,第4分位再度增高的J型曲线。全体对象中MS组分≥1个的比例组间比较具有统计学差异(P=0.016),肥胖儿童中MS发生比例亦具有统计学差异(P=0.044)。女孩中低脂联素血症的发生率随FGF21四分位变化亦表现为上述J型曲线。
4.logistic回归显示,全体儿童中FGF21水平的升高(OR=I.681,P=0.041)或者降低(OR=I.924,P=0.009)均与儿童携带MS组分的风险增加显著相关,肥胖儿童中FGF21的升高与儿童罹患MS风险的增加显著相关(OR=19.971,P=0.013),且这种风险度的增加独立于儿童的年龄、性别和BMI。
结论：
儿童人群中FGF21水平与肥胖无显著相关性。儿童人群中存在FGF21相对缺乏和FGF21抵抗两种状态。过低或过高的FGF21水平均与儿童不良代谢状况相关,提示全体儿童携带MS组分以及肥胖儿童罹患MS风险的增加。
Objective:
Recently, a novel protein, fibroblast growth factor21(FGF21) has gained a lot of attention due to its beneficial effects on glucose homeostasis and lipid metabolism in animal models. However, the physiological and pathologic roles of FGF21in human remain unclear. This study aimed to investigate the relationship between its serum levels and metabolic syndrome (MS) in children.
Methods:
820Chinese subjects aged6to18years were recruited from the Beijing Child and Adolescent Metabolic Syndrome study. Anthropometric parameters, fasting lipid profile, glucose, fasting insulin, leptin, adiponectin, resistin and FGF21were measured. MS was diagnosed according to the modified Adult Treatment Panel Ⅲ (ATPⅢ) criteria.
Results:
There was no sex difference in serum FGF21levels (P=0.082). A slightly increase in FGF21levels during middle puberty was observed in both genders.Though medians of FGF21levels in each group increased progressively from normal weight to overweight to obese, they did not reach statistical significant. FGF21levels in children with and without MS did not show significant difference either.
In the whole cohort, univariate association analysis between FGF21and waist circumference, body mass index (BMI), fat mass percentage, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose, insulin and fasting lipid profile showed that FGF21only had correlation with DBP (r=0.08, P=0.023), leptin (r=0.085, P=0.015) and resistin (r=0.078, P=0.027). Adjusted for age, gender and BMI, fasting blood glucose also correlated with FGF21(r=0.074, P=0.038)
The whole population was then divided into quartiles based on FGF21levels. The percentages of obese children in each group were almost the same. A J-shaped association of the incidences of MS and MS components with FGF21was observed. Both the first and the fouth quartiles were associated with higher incidences of carrying1or more MS components (P=0.016). MS incidences in groups of obese children divided according to the above quartiles also showed significant difference (P=0.044). A J-shaped association of hypoadiponectinemia with FGF21was also observed, but only in girls.
In the whole population, logistic regression analysis showed that both high (OR=1.681,P=0.041) and low(OR=1.924,P=0.009) levels of FGF21were associated with increased risk of carrying metabolic components in children, while in the obese subgroup, high level of FGF21was associated with increased risk of developing MS (OR=19.971, P=0.013),even after ajusting for age, gender and BMI.
Conclusion:
In this study, serum FGF21level did not correlate with obesity. A J-shaped association between FGF21levels and incidences of MS and MS components in children was observed, showing that not only higher level but also lower level of FGF21indicated adverse metabolic profiles.
引文
[1]Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta.2000; 1492(1):203-6.
[2]Dostalova I, Haluzikova D, Haluzik M. Fibroblast growth factor 21:a novel metabolic regulator with potential therapeutic properties in obesity/type 2 diabetes mellitus. Physiol Res.2009; 58(1):1-7.
[3]Long YC, Kharitonenkov A. Hormone-like fibroblast growth factors and metabolic regulation. Biochim Biophys Acta.2011; 1812(7):791-5.
[4]Kharitonenkov A. FGFs and metabolism. Curr Opin Pharmacol.2009; 9(6):805-10.
[5]Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab.2007; 5(6):426-37.
[6]Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS,Maratos-Flier E. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes.2010; 59(11):2781-9.
[7]Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV,et al.Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF 19 and FGF21.J Biol Chem. 2007; 282(37):26687-95.
[8]Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ,et al. FGF-21 as a novel metabolic regulator. J Clin Invest.2005; 115(6):1627-35.
[9]Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT,et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology.2007; 148(2):774-81.
[10]Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab.2008; 8(2):169-74.
[11]Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes.2008; 57(5):1246-53.
[12]Mai K, Schwarz F, Bobbert T, Andres J, Assmann A, Pfeiffer AF, et al. Relation between fibroblast growth factor-21, adiposity, metabolism, and weight reduction. Metabolism.2011; 60(2):306-11.
[13]Woelnerhanssen B, Peterli R, Steinert RE, Peters T, Borbely Y, Beglinger C. Effects of postbariatric surgery weight loss on adipokines and metabolic parameters: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy--a prospective randomized trial. Surg Obes Relat Dis.2011; 7(5):561-8.
[14]Tyynismaa H, Raivio T, Hakkarainen A, Ortega-Alonso A, Lundbom N, Kaprio J,et al. Liver fat but not other adiposity measures influence circulating FGF21 levels in healthy young adult twins. J Clin Endocrinol Metab.2011; 96(2):E351-5.
[15]Semba RD, Sun K, Egan JM, Crasto C, Carlson OD, Ferrucci L. Relationship of serum fibroblast growth factor 21 with abnormal glucose metabolism and insulin resistance:the Baltimore longitudinal study of aging. J Clin Endocrinol Metab.2012; 97(4):1375-82.
[16]Chen C, Cheung BM, Tso AW, Wang Y, Law LS, Ong KL, et al. High plasma level of fibroblast growth factor 21 is an Independent predictor of type 2 diabetes:a 5.4-year population-based prospective study in Chinese subjects. Diabetes Care. 2011; 34(9):2113-5.
[17]Cuevas-Ramos D, Almeda-Valdes P, Gomez-Perez FJ, Meza-Arana CE, Cruz-Bautista I, Arellano-Campos O, et al. Daily physical activity, fasting glucose, uric acid, and body mass index are independent factors associated with serum fibroblast growth factor 21 levels. Eur J Endocrinol.2010; 163(3):469-77.
[18]Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, Zhang H, et al. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol.2010; 53(5):934-40.
[19]Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B, Celikel CA, et al. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest. 2010;40(10):887-92.
[20]Lin Z, Wu Z, Yin X, Liu Y, Yan X, Lin S, et al. Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS One.2010; 5(12):e15534.
[21]Alberti KG, Zimmet P, Shaw J. Metabolic syndrome-a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med 2006; 23:469-480.
[22]Saland JM. Update on the metabolic syndrome in children. Curr Opin Pediatr 2007; 19:183-91.
[23]Mi J, Wang TY, Li M, et al. Epidemic of obesity and related metabolic syndrome among schoolchildrenin Beijing, China. Obesity Research.2005; 13(suppl):A30.
[24]Ghasemi A, Zahediasl S, Azizi F. Nitric oxide and clustering of metabolic syndrome components in pediatrics. Eur J Epidemiol 2010; 25:45-53.
[25]Gnacinska M, Malgorzewicz S, Stojek M, Lysiak-Szydlowska W, Sworczak K. Role of adipokines in complications related to obesity:a review. Adv Med Sci 2009; 54: 150-157.
[26]Mohan V, Deepa R, Pradeepa R, Vimaleswaran KS, Mohan A, Velmurugan K et al. Association of low adiponectin levels with the metabolic syndrome--the Chennai Urban Rural Epidemiology Study (CURES-4). Metabolism 2005; 54:476-481.
[27]Matsuzawa Y. The metabolic syndrome and adipocytokines. FEBS Lett 2006; 580: 2917-2921.
[28]Reinehr T, Woelfle J, Wunsch R, Roth CL. Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children:a longitudinal analysis. J Clin Endocrinol Metab.2012. Epub ahead of print.
[29]Hero M, Dunkel L, Vaaralahti K, Raivio T. Serum FGF21 in boys with idiopathic short stature:relationship to lipid profile, onset of puberty and growth. Clin Endocrinol (Oxf).2011. doi:10.1111/j.1365-2265.2011.03999.x.
[30]米杰,程红,侯冬青,等.2004年北京儿童青少年超重和肥胖流行现状.中华流行病学杂志,2006,27：474-479.
[31]中国肥胖问题工作组。中国学龄儿童青少年超重、肥胖筛查体重指数值分类标准.中华流行病学杂志,2004,25：97-102.
[32]Mi J, Munkonda MN, Li M, Zhang MX, Zhao XY, Fouejeu PC et al. Adiponectin and leptin metabolic biomarkers in chinese children and adolescents. J Obes 2010; 2010:892081.
[33]Li M, Fisette A, Zhao XY, Deng JY, Mi J, Cianflone K. Serum resistin correlates with central obesity but weakly with insulin resistance in Chinese children and adolescents. Int J Obes 2009; 33:424-439.
[34]Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of ametabolic syndrome phenotype in adolescents:findings from the third National Health and Nutrition Examination Survey,1988-1994. Arch Pediatr Adolesc Med 2003; 157:821-827.
[35]Mantzoros CS, Flier JS, Rogol AD. Longitudinal Assessment of Hormonal and Physical Alterations during Normal Puberty in Boys. V. Rising Leptin Levels May Signal the Onset of Puberty. J Clin Endocrinol Metab 82:1066-1070,1997.
[36]Moyers JS, Shiyanova TL, Mehrbod F, Dunbar JD, Noblitt TW, Otto KA, et al. Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling. J Cell Physiol.2007; 210(1):1-6.
[37]Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology.2008; 149(12):6018-27.
[38]Chen WW, Li L, Yang GY, Li K, Qi XY, Zhu W, et al. Circulating FGF-21 levels in normal subjects and in newly diagnose patients with Type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes.2008; 116(1):65-8.
[39]Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf). 2009;71(3):369-75.
[40]Matuszek B, Lenart-Lipinska M, Duma D, Solski J, Nowakowski A. Evaluation of concentrations of FGF-21-a new adipocytokine in type 2 diabetes. Endokrynol Pol. 2010; 61(1):50-4.
[41]Ge X, Chen C, Hui X, Wang Y, Lam KS, Xu A. Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. J Biol Chem.2011; 286(40):34533-41.
[2]Dostalova I, Haluzikova D, Haluzik M. Fibroblast growth factor 21:a novel metabolic regulator with potential therapeutic properties in obesity/type 2 diabetes mellitus. Physiol Res.2009; 58(1):1-7.
[3]Long YC, Kharitonenkov A. Hormone-like fibroblast growth factors and metabolic regulation. Biochim Biophys Acta.2011; 1812(7):791-5.
[4]Kharitonenkov A. FGFs and metabolism. Curr Opin Pharmacol.2009; 9(6):805-10.
[5]Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab.2007; 5(6):426-37.
[6]Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS,Maratos-Flier E. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes.2010; 59(11):2781-9.
[7]Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV,et al.Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF 19 and FGF21.J Biol Chem. 2007; 282(37):26687-95.
[8]Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ,et al. FGF-21 as a novel metabolic regulator. J Clin Invest.2005; 115(6):1627-35.
[9]Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT,et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology.2007; 148(2):774-81.
[10]Galman C, Lundasen T, Kharitonenkov A, Bina HA, Eriksson M, Hafstrom I et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab.2008; 8(2):169-74.
[11]Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes.2008; 57(5):1246-53.
[12]Mai K, Schwarz F, Bobbert T, Andres J, Assmann A, Pfeiffer AF, et al. Relation between fibroblast growth factor-21, adiposity, metabolism, and weight reduction. Metabolism.2011; 60(2):306-11.
[13]Woelnerhanssen B, Peterli R, Steinert RE, Peters T, Borbely Y, Beglinger C. Effects of postbariatric surgery weight loss on adipokines and metabolic parameters: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy--a prospective randomized trial. Surg Obes Relat Dis.2011; 7(5):561-8.
[14]Tyynismaa H, Raivio T, Hakkarainen A, Ortega-Alonso A, Lundbom N, Kaprio J,et al. Liver fat but not other adiposity measures influence circulating FGF21 levels in healthy young adult twins. J Clin Endocrinol Metab.2011; 96(2):E351-5.
[15]Semba RD, Sun K, Egan JM, Crasto C, Carlson OD, Ferrucci L. Relationship of serum fibroblast growth factor 21 with abnormal glucose metabolism and insulin resistance:the Baltimore longitudinal study of aging. J Clin Endocrinol Metab.2012; 97(4):1375-82.
[16]Chen C, Cheung BM, Tso AW, Wang Y, Law LS, Ong KL, et al. High plasma level of fibroblast growth factor 21 is an Independent predictor of type 2 diabetes:a 5.4-year population-based prospective study in Chinese subjects. Diabetes Care. 2011; 34(9):2113-5.
[17]Cuevas-Ramos D, Almeda-Valdes P, Gomez-Perez FJ, Meza-Arana CE, Cruz-Bautista I, Arellano-Campos O, et al. Daily physical activity, fasting glucose, uric acid, and body mass index are independent factors associated with serum fibroblast growth factor 21 levels. Eur J Endocrinol.2010; 163(3):469-77.
[18]Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, Zhang H, et al. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol.2010; 53(5):934-40.
[19]Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B, Celikel CA, et al. Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest. 2010;40(10):887-92.
[20]Lin Z, Wu Z, Yin X, Liu Y, Yan X, Lin S, et al. Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS One.2010; 5(12):e15534.
[21]Alberti KG, Zimmet P, Shaw J. Metabolic syndrome-a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med 2006; 23:469-480.
[22]Saland JM. Update on the metabolic syndrome in children. Curr Opin Pediatr 2007; 19:183-91.
[23]Mi J, Wang TY, Li M, et al. Epidemic of obesity and related metabolic syndrome among schoolchildrenin Beijing, China. Obesity Research.2005; 13(suppl):A30.
[24]Ghasemi A, Zahediasl S, Azizi F. Nitric oxide and clustering of metabolic syndrome components in pediatrics. Eur J Epidemiol 2010; 25:45-53.
[25]Gnacinska M, Malgorzewicz S, Stojek M, Lysiak-Szydlowska W, Sworczak K. Role of adipokines in complications related to obesity:a review. Adv Med Sci 2009; 54: 150-157.
[26]Mohan V, Deepa R, Pradeepa R, Vimaleswaran KS, Mohan A, Velmurugan K et al. Association of low adiponectin levels with the metabolic syndrome--the Chennai Urban Rural Epidemiology Study (CURES-4). Metabolism 2005; 54:476-481.
[27]Matsuzawa Y. The metabolic syndrome and adipocytokines. FEBS Lett 2006; 580: 2917-2921.
[28]Reinehr T, Woelfle J, Wunsch R, Roth CL. Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children:a longitudinal analysis. J Clin Endocrinol Metab.2012. Epub ahead of print.
[29]Hero M, Dunkel L, Vaaralahti K, Raivio T. Serum FGF21 in boys with idiopathic short stature:relationship to lipid profile, onset of puberty and growth. Clin Endocrinol (Oxf).2011. doi:10.1111/j.1365-2265.2011.03999.x.
[30]米杰,程红,侯冬青,等.2004年北京儿童青少年超重和肥胖流行现状.中华流行病学杂志,2006,27：474-479.
[31]中国肥胖问题工作组。中国学龄儿童青少年超重、肥胖筛查体重指数值分类标准.中华流行病学杂志,2004,25：97-102.
[32]Mi J, Munkonda MN, Li M, Zhang MX, Zhao XY, Fouejeu PC et al. Adiponectin and leptin metabolic biomarkers in chinese children and adolescents. J Obes 2010; 2010:892081.
[33]Li M, Fisette A, Zhao XY, Deng JY, Mi J, Cianflone K. Serum resistin correlates with central obesity but weakly with insulin resistance in Chinese children and adolescents. Int J Obes 2009; 33:424-439.
[34]Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of ametabolic syndrome phenotype in adolescents:findings from the third National Health and Nutrition Examination Survey,1988-1994. Arch Pediatr Adolesc Med 2003; 157:821-827.
[35]Mantzoros CS, Flier JS, Rogol AD. Longitudinal Assessment of Hormonal and Physical Alterations during Normal Puberty in Boys. V. Rising Leptin Levels May Signal the Onset of Puberty. J Clin Endocrinol Metab 82:1066-1070,1997.
[36]Moyers JS, Shiyanova TL, Mehrbod F, Dunbar JD, Noblitt TW, Otto KA, et al. Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling. J Cell Physiol.2007; 210(1):1-6.
[37]Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology.2008; 149(12):6018-27.
[38]Chen WW, Li L, Yang GY, Li K, Qi XY, Zhu W, et al. Circulating FGF-21 levels in normal subjects and in newly diagnose patients with Type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes.2008; 116(1):65-8.
[39]Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D, et al. Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf). 2009;71(3):369-75.
[40]Matuszek B, Lenart-Lipinska M, Duma D, Solski J, Nowakowski A. Evaluation of concentrations of FGF-21-a new adipocytokine in type 2 diabetes. Endokrynol Pol. 2010; 61(1):50-4.
[41]Ge X, Chen C, Hui X, Wang Y, Lam KS, Xu A. Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. J Biol Chem.2011; 286(40):34533-41.