运动防肥减肥的分子机制研究
摘要
随着社会文明的发展与进步，物质生活水平不断提高，体重超过标准的肥胖者越来越多，已成为当今世界所面临的严峻的公共健康问题。过于肥胖不仅影响外观形象，给工作生活带来诸多不便，且与冠心病、动脉粥样硬化、高血压、糖尿病及某些肿瘤的发生密切相关。因此，防治肥胖已成为提高人们健康水平的重要研究课题。有氧运动作为防肥减肥的一种合理手段已被广泛认可，随着科学研究手段的进步以及研究层次的不断拓展与深入，研究发现，骨骼肌UCP_3很可能是影响运动时能量消耗及运动后静息代谢率的重要因素之一。
本实验旨在通过观察不同形式的急性有氧运动(跑台运动和游泳运动)对SD雄性大鼠骨骼肌UCP_3mRNA表达水平的影响及急性有氧运动后骨骼肌UCP_3mRNA过表达的时相性变化规律，分析骨骼肌UCP_3mRNA表达水平与脂肪分解相关指标(血FFA和血Leptin)之间的内在联系，为科学的选择运动方式、强度、持续时间、练习时间间隔、练习频率，制订防肥减肥健身运动处方提供理论依据。
结果表明：(1)急性有氧运动(跑台运动和游泳运动)确实可以通过提高骨骼肌UCP_3mRNA表达水平，起到防治肥胖的作用；(2)不同形式的急性有氧运动对骨骼肌UCP_3mRNA表达水平的影响程度不同，游泳运动与跑台运动相比更能促进骨骼肌UCP_3mRNA表达，这可能与游泳运动所处的特殊的水环境有关，可能在运动强度和刺激形式上游泳与跑台运动有所差别所致；(3)急性有氧运动对骨骼肌UCP_3mRNA表达水平产生时相性影响，且这种影响受到许多因素的制约，包括运动形式、运动强度、血游离FFA浓度、禁食状态、激素水平等。
With the development of society and the increasing living standard, the incidence of obesity is increasing year by year, which has been a serious human health problem in the world. Obesity prevention and treatment has been a principal task to improve human health. As a method to treat obesity, aerobic exercise has been accepted extensively. With the extension of scientific research methods, it suggests that UCP3 of skeletal muscle is likely to one of the most important factors to affect energy consume during exercise and resting metabolic rate after exercise.
The purpose of this experiment is to observe the influence of different acute aerobic exercises on UCP3mRNA expression level of SD male rat and analyze internal relation between UCP;imRNA expression level and content of serum FFA and serum Leptin. This research provide theoretical basement to scientifically select pattern, intension, duration, interval, frequency of exercises, and make, reasonable exercise prescription.
The results show that (1) acute aerobic exercise can treat obesity by up-regulate UCPjnRNA expression; (2) different acute aerobic exercises have different effects on UCP3mRNA expression, swimming exercise can up-regulate UCP3mRNA expression more than treadmill running, this maybe relevant to special environment of swimming exercise. Additionally it may be different from treadmill exercise in intension and stimulation ; (3) Acute aerobic exercises have periodic effect on muscle UCPjmRNA expression, which is affected by many factors including exercise pattern, intention, fast, serum FFA, hormone level.
本实验旨在通过观察不同形式的急性有氧运动(跑台运动和游泳运动)对SD雄性大鼠骨骼肌UCP_3mRNA表达水平的影响及急性有氧运动后骨骼肌UCP_3mRNA过表达的时相性变化规律，分析骨骼肌UCP_3mRNA表达水平与脂肪分解相关指标(血FFA和血Leptin)之间的内在联系，为科学的选择运动方式、强度、持续时间、练习时间间隔、练习频率，制订防肥减肥健身运动处方提供理论依据。
结果表明：(1)急性有氧运动(跑台运动和游泳运动)确实可以通过提高骨骼肌UCP_3mRNA表达水平，起到防治肥胖的作用；(2)不同形式的急性有氧运动对骨骼肌UCP_3mRNA表达水平的影响程度不同，游泳运动与跑台运动相比更能促进骨骼肌UCP_3mRNA表达，这可能与游泳运动所处的特殊的水环境有关，可能在运动强度和刺激形式上游泳与跑台运动有所差别所致；(3)急性有氧运动对骨骼肌UCP_3mRNA表达水平产生时相性影响，且这种影响受到许多因素的制约，包括运动形式、运动强度、血游离FFA浓度、禁食状态、激素水平等。
With the development of society and the increasing living standard, the incidence of obesity is increasing year by year, which has been a serious human health problem in the world. Obesity prevention and treatment has been a principal task to improve human health. As a method to treat obesity, aerobic exercise has been accepted extensively. With the extension of scientific research methods, it suggests that UCP3 of skeletal muscle is likely to one of the most important factors to affect energy consume during exercise and resting metabolic rate after exercise.
The purpose of this experiment is to observe the influence of different acute aerobic exercises on UCP3mRNA expression level of SD male rat and analyze internal relation between UCP;imRNA expression level and content of serum FFA and serum Leptin. This research provide theoretical basement to scientifically select pattern, intension, duration, interval, frequency of exercises, and make, reasonable exercise prescription.
The results show that (1) acute aerobic exercise can treat obesity by up-regulate UCPjnRNA expression; (2) different acute aerobic exercises have different effects on UCP3mRNA expression, swimming exercise can up-regulate UCP3mRNA expression more than treadmill running, this maybe relevant to special environment of swimming exercise. Additionally it may be different from treadmill exercise in intension and stimulation ; (3) Acute aerobic exercises have periodic effect on muscle UCPjmRNA expression, which is affected by many factors including exercise pattern, intention, fast, serum FFA, hormone level.
引文
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2． Arvaniti K, et al. Leptin and corticosterone have opposite effects on food intake and the expression of UCP1 mRNA in brown adipose tissue of lepob/lepob mice [J].Endocrinology. 1998; 139(9) : 4000-4003．
3． Bao S, Kennedy A,Wojciechowshki B, et al. Diabetes. 1998; 47:1809-1814．
4． Bianco AC, et al. Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis [J]. Journal of Biological Chemistry 1988; 263(34) :18168-175．
5． Bonet ML,et al.Vitamin a status affects rodent brown adipose tissue thermogenic capacity[J].Int J Obesity. 1998; 22:5153．
6． Bouillaud F, A sequence related to a DNA recognition element is essential for the inhibition by nucleotides of proton transport through the mitochondria uncoupling protein [J].EMBO Journal. 1994;13(8) :1990-1997．
7． Brand M. D, The significance and mechanism of mitochondrial proton conductance [J].Int J Obes. 1999;23(6) :S4-S11．
8． Cassard AM, et al. Human uncoupling protein gene: Structure, comparison with rat gene, and assignment to the long arm of chromosome 4 [J]. Journal of Cellular Biochemistry. 1990;4(3) : 255-264．
9． Colditz GA, Willett WC, Rotnitsky A, et al. Weight gain as a risk factor for clinical diabetes in women [J].Arch Int Med. 1995; 122:481-486．
10． Collins S, et al. Regulation of the uncoupling protein genes(UCP-1,-2,-3) by nutrients and hormones. 8th International Congress on Obesity [J]. Hot Topic. Abstracts 1998; LA236．
11． Deurenberg Yag M, Yian TB, Kai CS, Deurenberg P, van Staveren WA. Manifestation of cardiovascular risk factors at low levels of body mass index and waist-to-hip ratio in Singaporean Chinese [J]. Asia Pacific J Clin Nutr. 1999;8(3) :177-183．
12． Despres J P, Moor jani S, Lupien P J et al. Regional Distribution of Body Fat, Plasma Liporoteins, and Cardiovascular Disease [J]. Arteriosclerosis. 1990; 10: 497-511．
13． Emilsson V, Summers RT, Hamilton S, et al. Biochem Biophys Res Commun. 1998; 252:450-454．
14． Gagnon J, et al.DNA polymorphism in the uncoupling protein 1 (UCP1) gene has no effect on obesity related phenotypes in the Swedish Obese Subjects cohorts [J].Int J Obes 1998; 22(6) :500-505．
15． Gong Da-Wei,et al. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta 3-adrenergic agonists, and leptin [J]. Journal of Biological Chemistry 1997; 272 (39) :24129-24132．
16． Hakkarainen V, et al. Impact of ALA55VAL polynorphism in UCP2 gene on body composition and basal metabolic rate in obese Finns [J]. Int J Obesity 1998; 22(Suppl 3) :S7．
17． Hildebrandt AL, Neufer PD. Exercise attenuates the fasting-induced transcriptional activation of metabolic genes in skeletal muscle [J]. Am J Physiol Endocrinol Metab. 2000, 278(6) :E1087-86．
18． Kaisaki PJ, et al. Localization of tub and uncoupling proteins (Ucp) 2 and 3 to a region of rat Chromosome 1 linked to glucose intolerance and adiposity in the Goto-Kakizaki (GK) Type 2 diabetic rat [J]. Mammalian Genome 1998; 9(11) :910-912．
19． Kennel WB, DAgostino RB, Cobb JL. Effect of weigh onCardiovascular Disease. Am J Clin Nutr [J].1996; 63(Suppl.4) :19s-22s.
20． Kelly L. J,et al. Peroxisome proliferator-activated receptors gamma and (10U*(8U mediate in vivo regulation of uncoupling protein (UCP1, UCP-2, UCP-3) gene expression [J]. Endocrinology 1998; 139(12) : 4920-4927．
21． Kenette GA. [J]. Drugs, 1998; 56(1) :456-470．
22． Klaus S, et al. Characterization of the novel brown adipocyte cell line HIB 1B. Adrenergic pathways involved in regulation of uncoupling protein gene expression[J]. Journal of Cell Science 1994; 107(1) :313-319．
23． Kozak LP, et al. Mitochondrial uncoupling proteins and obesity:Molecular and genetic aspects of UCP1 [J]. Int J Obes 1999; 23(6) :33-37．
24． Ko GTC, Chan JCN, Cockram CS, Woo J. Prediction of hypertention,
diabetes, dyslipidacmia or albuminoidal using simple anthropometries indexes in Hong Kong Chinese [J].Int J Obes 1999,23(11) :1136-42．
25． Krook A, Digby J, O' Rahilly S, et al. Diabetes. 1998; 47:1528-1531．
26． Lean MEJ, Hans TS, Seidell JC. Impairment of health and quality life in people with large waist circumference [J]. Lancet. 1998, 351:853-856．
27． Lentes KU, et al. Genomic organization and mutational analysis of the human UCP2 gene, a prime candidate gene for human obesity gene, a prime candidate gene for human obesity [J].J Recept Signal Transduct Res. 1999;19(1-4) :229-224．
28． Li B, Nolte LA, Ju JS, et al. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice [J].Nat Med . 2000; 6(10) :1115-1120．
29． Luyckx FH, et al. Influence of the A-->G (-3826) uncoupling protein-1 gene(UCP1) variant on the dynamics of body weight before and after gastroplasty in morbidly obese subjects [J]. Int J Obes. 1998; 22(12) :1244-1245．
30． Mao W. G, et al. UCP4, a novel bain-specific mitochondrial protein that reduces membrane potential in mammalian cells [J]. FEBS Lett. 1999; 443(3) :326-330．
31． Micheal H, Hauptman J, Di Girolamo M. [J].JA-MA, 1999,281(3) :235-242．
32． Nordfors L, et al. Reduced gene expression of UCP2 but not UCP3 in skeletal muscle of human obese subjects[J]. Diabetologia. 1998; 41(8) :935-939．
33． Oberkofler H, Liu YM, Esterbauer H, et al. Diabetologia. 1998; 41:940-946．
34． Otabe S, Clement K, et al. A genetic variation in the 5' flanking region of UCP3 gene is associated with body mass index in humans in interaction with physical activity [J]. Diabetologia. 2000, 43(2) :245-249．
35． Park IRA, et al. Neural influences on trophic changes in brown adipose tissue during cold acclimation [J].American Journal of Physiology. 1998; 255(6) :R874-R881．
36． Pedersen SB, Lund s, Buhl ES, et al. Insulin and contraction directly stimulate UCP2 and UCP3 mRNA expression in rat skeletal
muscle in Vitro [J]. Biochem Biophy Res Commun.2001; 283(1) :19-25．
37． Ronald N. Et al.Regulation of skeletal muscle UCP2 and UCP3 gene expression by exercise and denervation [J].Am. J.Physiol. Endocrinol. Metab. 1999;276(1) :217-221．
38． Sadurskis A,et al.Polyunsaturated fatty acids recruit brown adipose tissue: Increased UCP content and NST capacity [J]. Physiol Endocrinol Metab. 1995;269(2) :351-360．
39． Schrauwen P. et al. Skeletal muscle UCP2 and UCP3 expression in trained and untrained male sudjects[J].Int. J. Obes. 1999;23(9) :966-972．
40． Schrauwen P. et al. Fiber type dependent upregulation of human skeletal muscle UCP2 and UCP3 mRNA expression by high-fat diet [J]. Int J Relat Metab Disord. 2001;25(4) :449-456．
41． Sedletskii II, et al. The immune status of patients with obesity [J].Vraeh Delo.1990;9:71-73．
42． Solanes a, et al. The human Uncoupling protein-3 gene. Genomicstructure, chromosomal localisation, and genetic basis for short and long from transcripts [J].J Biol Chem. 1997． 272:25433-25436．
43． Stenlof W, et al. Low basal metabolic rate is associated with low levels of uncoupling protein-2 mRNA levels in humans [J]. Int J Obesity. 1998; 22(Supp1 3) :S15．
44． Stphens TW, et al. The role neuropeptide Y in the antiobesity action of the obese gene product [J].Nature.1995:377:530．
45． Surwit RS. Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice [J]. Proc. Natl. Acad. Sci. USA. 1998; 95(7) :4061-4065．
46． Tanaka S, et al. Imparied immunity in obesity: suppressed but reversible lymphocyte responsiveness [J]. Int J obesity. 1993; 17:631-636．
47． Tartagia LA et al. Identification and expression cloning of a leptin receptor,OB-R[J].Cell. 1996; 84:491-500．
48． Trisha Gura . Uncoupling proteins provide new clue to obesity' s causes [J] . Science. 1998; 280: 1369-1370．
49． Tsuboyama-Kasaoka N, et al. Overexpression of GLUT4 in mice causes up-regulation of UCP3 mRNA in skeletal muscle [J]. Biochem Biophys Res Commun. 1999;258(1) :187-193．
50. Ueshima H et al. Mortality of cardiovascular disease in respect of BMI[J]. Research report of the grant of Ministry of Health and Welfare 1998. Tokyo Janpan.
51. Walder K, et al. Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism obesity in Pima Indians. Hum Mol Genet. 1998; 7(9):1431-1435.
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61．郑以漫等．解偶联蛋白2基因Ala55Val变异与中国人2型糖尿病患者葡萄糖兴奋后胰岛素分泌功能的关系[J]．中华内分泌代谢杂志，1999；15(4)：199—202．
2． Arvaniti K, et al. Leptin and corticosterone have opposite effects on food intake and the expression of UCP1 mRNA in brown adipose tissue of lepob/lepob mice [J].Endocrinology. 1998; 139(9) : 4000-4003．
3． Bao S, Kennedy A,Wojciechowshki B, et al. Diabetes. 1998; 47:1809-1814．
4． Bianco AC, et al. Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis [J]. Journal of Biological Chemistry 1988; 263(34) :18168-175．
5． Bonet ML,et al.Vitamin a status affects rodent brown adipose tissue thermogenic capacity[J].Int J Obesity. 1998; 22:5153．
6． Bouillaud F, A sequence related to a DNA recognition element is essential for the inhibition by nucleotides of proton transport through the mitochondria uncoupling protein [J].EMBO Journal. 1994;13(8) :1990-1997．
7． Brand M. D, The significance and mechanism of mitochondrial proton conductance [J].Int J Obes. 1999;23(6) :S4-S11．
8． Cassard AM, et al. Human uncoupling protein gene: Structure, comparison with rat gene, and assignment to the long arm of chromosome 4 [J]. Journal of Cellular Biochemistry. 1990;4(3) : 255-264．
9． Colditz GA, Willett WC, Rotnitsky A, et al. Weight gain as a risk factor for clinical diabetes in women [J].Arch Int Med. 1995; 122:481-486．
10． Collins S, et al. Regulation of the uncoupling protein genes(UCP-1,-2,-3) by nutrients and hormones. 8th International Congress on Obesity [J]. Hot Topic. Abstracts 1998; LA236．
11． Deurenberg Yag M, Yian TB, Kai CS, Deurenberg P, van Staveren WA. Manifestation of cardiovascular risk factors at low levels of body mass index and waist-to-hip ratio in Singaporean Chinese [J]. Asia Pacific J Clin Nutr. 1999;8(3) :177-183．
12． Despres J P, Moor jani S, Lupien P J et al. Regional Distribution of Body Fat, Plasma Liporoteins, and Cardiovascular Disease [J]. Arteriosclerosis. 1990; 10: 497-511．
13． Emilsson V, Summers RT, Hamilton S, et al. Biochem Biophys Res Commun. 1998; 252:450-454．
14． Gagnon J, et al.DNA polymorphism in the uncoupling protein 1 (UCP1) gene has no effect on obesity related phenotypes in the Swedish Obese Subjects cohorts [J].Int J Obes 1998; 22(6) :500-505．
15． Gong Da-Wei,et al. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta 3-adrenergic agonists, and leptin [J]. Journal of Biological Chemistry 1997; 272 (39) :24129-24132．
16． Hakkarainen V, et al. Impact of ALA55VAL polynorphism in UCP2 gene on body composition and basal metabolic rate in obese Finns [J]. Int J Obesity 1998; 22(Suppl 3) :S7．
17． Hildebrandt AL, Neufer PD. Exercise attenuates the fasting-induced transcriptional activation of metabolic genes in skeletal muscle [J]. Am J Physiol Endocrinol Metab. 2000, 278(6) :E1087-86．
18． Kaisaki PJ, et al. Localization of tub and uncoupling proteins (Ucp) 2 and 3 to a region of rat Chromosome 1 linked to glucose intolerance and adiposity in the Goto-Kakizaki (GK) Type 2 diabetic rat [J]. Mammalian Genome 1998; 9(11) :910-912．
19． Kennel WB, DAgostino RB, Cobb JL. Effect of weigh onCardiovascular Disease. Am J Clin Nutr [J].1996; 63(Suppl.4) :19s-22s.
20． Kelly L. J,et al. Peroxisome proliferator-activated receptors gamma and (10U*(8U mediate in vivo regulation of uncoupling protein (UCP1, UCP-2, UCP-3) gene expression [J]. Endocrinology 1998; 139(12) : 4920-4927．
21． Kenette GA. [J]. Drugs, 1998; 56(1) :456-470．
22． Klaus S, et al. Characterization of the novel brown adipocyte cell line HIB 1B. Adrenergic pathways involved in regulation of uncoupling protein gene expression[J]. Journal of Cell Science 1994; 107(1) :313-319．
23． Kozak LP, et al. Mitochondrial uncoupling proteins and obesity:Molecular and genetic aspects of UCP1 [J]. Int J Obes 1999; 23(6) :33-37．
24． Ko GTC, Chan JCN, Cockram CS, Woo J. Prediction of hypertention,
diabetes, dyslipidacmia or albuminoidal using simple anthropometries indexes in Hong Kong Chinese [J].Int J Obes 1999,23(11) :1136-42．
25． Krook A, Digby J, O' Rahilly S, et al. Diabetes. 1998; 47:1528-1531．
26． Lean MEJ, Hans TS, Seidell JC. Impairment of health and quality life in people with large waist circumference [J]. Lancet. 1998, 351:853-856．
27． Lentes KU, et al. Genomic organization and mutational analysis of the human UCP2 gene, a prime candidate gene for human obesity gene, a prime candidate gene for human obesity [J].J Recept Signal Transduct Res. 1999;19(1-4) :229-224．
28． Li B, Nolte LA, Ju JS, et al. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice [J].Nat Med . 2000; 6(10) :1115-1120．
29． Luyckx FH, et al. Influence of the A-->G (-3826) uncoupling protein-1 gene(UCP1) variant on the dynamics of body weight before and after gastroplasty in morbidly obese subjects [J]. Int J Obes. 1998; 22(12) :1244-1245．
30． Mao W. G, et al. UCP4, a novel bain-specific mitochondrial protein that reduces membrane potential in mammalian cells [J]. FEBS Lett. 1999; 443(3) :326-330．
31． Micheal H, Hauptman J, Di Girolamo M. [J].JA-MA, 1999,281(3) :235-242．
32． Nordfors L, et al. Reduced gene expression of UCP2 but not UCP3 in skeletal muscle of human obese subjects[J]. Diabetologia. 1998; 41(8) :935-939．
33． Oberkofler H, Liu YM, Esterbauer H, et al. Diabetologia. 1998; 41:940-946．
34． Otabe S, Clement K, et al. A genetic variation in the 5' flanking region of UCP3 gene is associated with body mass index in humans in interaction with physical activity [J]. Diabetologia. 2000, 43(2) :245-249．
35． Park IRA, et al. Neural influences on trophic changes in brown adipose tissue during cold acclimation [J].American Journal of Physiology. 1998; 255(6) :R874-R881．
36． Pedersen SB, Lund s, Buhl ES, et al. Insulin and contraction directly stimulate UCP2 and UCP3 mRNA expression in rat skeletal
muscle in Vitro [J]. Biochem Biophy Res Commun.2001; 283(1) :19-25．
37． Ronald N. Et al.Regulation of skeletal muscle UCP2 and UCP3 gene expression by exercise and denervation [J].Am. J.Physiol. Endocrinol. Metab. 1999;276(1) :217-221．
38． Sadurskis A,et al.Polyunsaturated fatty acids recruit brown adipose tissue: Increased UCP content and NST capacity [J]. Physiol Endocrinol Metab. 1995;269(2) :351-360．
39． Schrauwen P. et al. Skeletal muscle UCP2 and UCP3 expression in trained and untrained male sudjects[J].Int. J. Obes. 1999;23(9) :966-972．
40． Schrauwen P. et al. Fiber type dependent upregulation of human skeletal muscle UCP2 and UCP3 mRNA expression by high-fat diet [J]. Int J Relat Metab Disord. 2001;25(4) :449-456．
41． Sedletskii II, et al. The immune status of patients with obesity [J].Vraeh Delo.1990;9:71-73．
42． Solanes a, et al. The human Uncoupling protein-3 gene. Genomicstructure, chromosomal localisation, and genetic basis for short and long from transcripts [J].J Biol Chem. 1997． 272:25433-25436．
43． Stenlof W, et al. Low basal metabolic rate is associated with low levels of uncoupling protein-2 mRNA levels in humans [J]. Int J Obesity. 1998; 22(Supp1 3) :S15．
44． Stphens TW, et al. The role neuropeptide Y in the antiobesity action of the obese gene product [J].Nature.1995:377:530．
45． Surwit RS. Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice [J]. Proc. Natl. Acad. Sci. USA. 1998; 95(7) :4061-4065．
46． Tanaka S, et al. Imparied immunity in obesity: suppressed but reversible lymphocyte responsiveness [J]. Int J obesity. 1993; 17:631-636．
47． Tartagia LA et al. Identification and expression cloning of a leptin receptor,OB-R[J].Cell. 1996; 84:491-500．
48． Trisha Gura . Uncoupling proteins provide new clue to obesity' s causes [J] . Science. 1998; 280: 1369-1370．
49． Tsuboyama-Kasaoka N, et al. Overexpression of GLUT4 in mice causes up-regulation of UCP3 mRNA in skeletal muscle [J]. Biochem Biophys Res Commun. 1999;258(1) :187-193．
50. Ueshima H et al. Mortality of cardiovascular disease in respect of BMI[J]. Research report of the grant of Ministry of Health and Welfare 1998. Tokyo Janpan.
51. Walder K, et al. Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism obesity in Pima Indians. Hum Mol Genet. 1998; 7(9):1431-1435.
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