SIRT1在肥胖、胰岛素抵抗发生机制中的作用
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摘要
第一部分：SIRT1单核苷酸变异与中国人群超重的相关性研究
目的：肥胖是遗传与环境因素相互作用所导致的疾病。随着分子遗传学的快速发展,使得在基因水平上筛选肥胖的易感基因成为可能。SNP是重要的遗传标记,其相关研究有助于理解遗传因素对肥胖症发病的影响。SIRT1是一种烟酰胺腺嘌呤二核苷酸(NAD+)依赖性去乙酰化酶,已有基于白种人的研究证明SIRT1某些的SNP位点变异与能量消耗减少及肥胖相关。因此,我们拟研究SIRT1中国人群常见基因型变异型与超重是否有关。
方法：依据连锁不平衡原理,从HapMap数据库SIRT1及其邻近区域常见SNP位点(最小基因型频率≥0.05%)中,按照覆盖绝大多数SIRT1基因的变异性的原则,我们选出四种单倍型标签SNP。然后通过PCR扩增和连接酶检测反应,检测了820名中国人的SIRT1基因型并分析其与超重肥胖的关系。
结果：基因型rs10509291AA和rs10823116 GG的频率在超重人群中明显增高,而基因型rs7894483TT的频率明显减低。rs10509291AT携带者超重风险较高,其基因型A符合显性基因模型。两种单倍型的携带者ATAA (rs7894483/rs10823116)和ATAG与AAAG (P<0.01)相比,表现出明显的高超重风险(OR:17.11和5.12)。TTATAA或TTATGG [rs10509291 /rs7894483 /rs10823116]的携带者分别比TTATAA或TTATGG [rs10509291 /rs7894483 /rs10823116]携带者超重风险低,该结果与rs10509291TT基因型携带者超重风险降低一致。
结论：本研究结果表明基因型rs10509291,rs7894483,和rs10823116 SNP相互作用,并且与中国人群超重明显相关。
第二部分：SIRT1在追赶生长大鼠腹性肥胖和胰岛素抵抗形成中的作用
目的：低营养水平者之营养提升过快,即可在一过性的生长抑制后出现快速生长的现象,称之为追赶生长。追赶生长会引起大鼠内脏脂肪沉积,腹型肥胖并导致全身胰岛素抵抗。SIRT1是一种烟酰胺腺嘌呤二核苷酸(NAD+)依赖性去乙酰化酶,它在胰岛素敏感性调控中有重要作用。我们拟观察追赶生长对SIRT1表达水平及其活性的影响,并用白藜芦醇来干预追赶生长大鼠模型,提高SIRT1的活性,从而减少线粒体功能损伤的负面效应。从而了解SIRT1在追赶生长胰岛素抵抗形成中的作用。
方法：采用热卡限制4周后予正常饮食8周构建营养快速提升所致成年期追赶生长大鼠模型。我们将8周龄的大鼠分为三组：正常对照组(NC),追赶生长组(CUG)和追赶生长白藜芦醇干预组(CUGE)。在喂养4周和8周以后分别检测每组大鼠的脂肪分布,骨骼肌和全身胰岛素抵抗情况。同时评价骨骼肌线粒体数量和功能、氧化应激水平及抗氧化酶活性。
结果：追赶生长可引起SIRT1活性的下降,腹部脂肪量增加,并导致系统及骨骼肌胰岛素抵抗形成,表现为60-120分钟的葡萄糖平均输注速率(30%,P<0.05)和骨骼肌葡萄糖摄取率(42%,P<0.05)明显下降；线粒体柠檬酸合酶活性下降；肌膜下和肌纤维间的线粒体复合体Ⅰ-Ⅳ活性下降20-40%(P<0.05),并且肌膜下的下降得更为明显。在肌膜下和肌纤维间的线粒体中,活性氧和丙二醛的水平在是明显升高的,而抗氧化酶活性是降低的。然而,口服SIRT1激动剂白藜芦醇能增加SIRT1活性、减少腹部脂肪,增加骨骼肌线粒体数量和改善胰岛素敏感性(43%,P<0.05)。白藜芦醇还能降低脂质过氧化反应和活性氧,恢复抗氧化酶的活性。
结论：本次实验表明了追赶生长可导致SIRT1表达及活性的降低,SIRT1激动剂白藜芦醇能增加SIRT1的表达及活性,通过增加骨骼肌线粒体复合体活性和加强抗氧化防御体系,来改善追赶生长大鼠的胰岛素敏感性。因此,SIRT1在大鼠腹部脂肪沉积、腹型肥胖胰岛素抵抗的形成中有重要的作用。
PART I:Three single nucleotide variants of SIRT1 gene are associated with overweight in a Chinese population
Objective:The prevalence of obesity and metabolic syndrome has fueled research on genetic loci of candidate genes. We herein aimed to explore whether common allelic variations in the SIRT1 gene were associated with overweight in a Chinese cohort.
Methods:Four haplotype-tagging single nucleotide polymorphisms (SNPs) were chosen for linkage disequilibrium, prevalence≥2.0%, minor allele frequency≥0.05, and coverage of the SIRT1 variability. They were genotyped in 820 Chinese individuals by PCR amplification and the ligase detection reaction.
Results:The rs1050929AA and rs10823116 GG alleles had significantly higher occurrence rates in the overweight group whereas the rs7894483TT alleles had a significantly lower rate. The association of carriers of rs10509291AT with modestly higher risk of overweight was consistent with a dominant model for the A allele. Carriers of two haplotypes, ATAA (rs7894483/rs10823116) and ATAG showed a significantly higher risk (OR:17.11 and 5.12) of overweight compared with carriers of AAAG (P<0.01). In agreement with a reduced risk of overweight in carriers of rs10509291TT genotype, carriers of TTATAA or TTATGG [rs10509291/rs7894483/rs10823116] had a lower risk of overweight than carriers of ATAA(OR:13.88 vs 17.11) and ATGG (OR:1.14 vs 5.12), respectively.
Conclusions:The findings of this study suggest that the rs10509291, rs7894483, and rs10823116 SNP alleles interact and have a significant association with excess weight gain in the Chinese population.
PARTⅡ:Resveratrol-activated SIRT1 Improves insulin resisitance in Catch-up Growth Rats
Objective:Caloric restriction (CR) followed by re-feeding, a phenomenon known as catch-up growth (CUG), affects mitochondrial function and results in systemic insulin resistance (IR). We intended to observe the effect of CUG on SIRTl expression and activity, and to increase SIRT1 activity, we interfered the rats with resveratrol, thus relieving the negative effects of mitochondrial dysfunction.
Methods:Rats (8 weeks of age) were divided into three groups:normal chow (NC), CUG, and catch-up growth with RES intervention (CUGE). Fat distribution, skeletal muscle and systemic IR were measured in each group after 4 and 8 weeks. Mitochondrial biogenesis and function, oxidative stress levels, and antioxidant enzyme activity in skeletal muscle were assessed.
Results:CUG induced IR resulted in significant reductions in both average glucose infusion rate60-120 (GIR60-120) at euglycemia and skeletal muscle glucose uptake. Mitochondrial citrate synthase (CS) activity was lower and activity of complexesⅠ-Ⅳin the intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondria were reduced by 20-40%, with the decrease being more pronounced in the SS fraction. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly higher in IMF and SS mitochondria while antioxidant enzyme activity was decreased. However, oral administration of RES increased SIRT1 activity, reduced abdominal fat accumulation, improved mitochondrial number and insulin sensitivity. RES treatment decreased levels of lipid peroxides and ROS, and restored antioxidant enzyme activity.
Conclusions:We investigated the potential of RES in CUG to prevent IR by increasing activity of the mitochondrial respiratory chain and antioxidant enzymes in skeletal muscle. This study demonstrates that SIRT1 protects insulin sensitivity by improving the activity of skeletal muscle mitochondrial complexes and the antioxidant defense status in CUG rats. Thus, SIRT1 has therapeutic potential for preventing CUG-related metabolic disorders.
目的：肥胖是遗传与环境因素相互作用所导致的疾病。随着分子遗传学的快速发展,使得在基因水平上筛选肥胖的易感基因成为可能。SNP是重要的遗传标记,其相关研究有助于理解遗传因素对肥胖症发病的影响。SIRT1是一种烟酰胺腺嘌呤二核苷酸(NAD+)依赖性去乙酰化酶,已有基于白种人的研究证明SIRT1某些的SNP位点变异与能量消耗减少及肥胖相关。因此,我们拟研究SIRT1中国人群常见基因型变异型与超重是否有关。
方法：依据连锁不平衡原理,从HapMap数据库SIRT1及其邻近区域常见SNP位点(最小基因型频率≥0.05%)中,按照覆盖绝大多数SIRT1基因的变异性的原则,我们选出四种单倍型标签SNP。然后通过PCR扩增和连接酶检测反应,检测了820名中国人的SIRT1基因型并分析其与超重肥胖的关系。
结果：基因型rs10509291AA和rs10823116 GG的频率在超重人群中明显增高,而基因型rs7894483TT的频率明显减低。rs10509291AT携带者超重风险较高,其基因型A符合显性基因模型。两种单倍型的携带者ATAA (rs7894483/rs10823116)和ATAG与AAAG (P<0.01)相比,表现出明显的高超重风险(OR:17.11和5.12)。TTATAA或TTATGG [rs10509291 /rs7894483 /rs10823116]的携带者分别比TTATAA或TTATGG [rs10509291 /rs7894483 /rs10823116]携带者超重风险低,该结果与rs10509291TT基因型携带者超重风险降低一致。
结论：本研究结果表明基因型rs10509291,rs7894483,和rs10823116 SNP相互作用,并且与中国人群超重明显相关。
第二部分：SIRT1在追赶生长大鼠腹性肥胖和胰岛素抵抗形成中的作用
目的：低营养水平者之营养提升过快,即可在一过性的生长抑制后出现快速生长的现象,称之为追赶生长。追赶生长会引起大鼠内脏脂肪沉积,腹型肥胖并导致全身胰岛素抵抗。SIRT1是一种烟酰胺腺嘌呤二核苷酸(NAD+)依赖性去乙酰化酶,它在胰岛素敏感性调控中有重要作用。我们拟观察追赶生长对SIRT1表达水平及其活性的影响,并用白藜芦醇来干预追赶生长大鼠模型,提高SIRT1的活性,从而减少线粒体功能损伤的负面效应。从而了解SIRT1在追赶生长胰岛素抵抗形成中的作用。
方法：采用热卡限制4周后予正常饮食8周构建营养快速提升所致成年期追赶生长大鼠模型。我们将8周龄的大鼠分为三组：正常对照组(NC),追赶生长组(CUG)和追赶生长白藜芦醇干预组(CUGE)。在喂养4周和8周以后分别检测每组大鼠的脂肪分布,骨骼肌和全身胰岛素抵抗情况。同时评价骨骼肌线粒体数量和功能、氧化应激水平及抗氧化酶活性。
结果：追赶生长可引起SIRT1活性的下降,腹部脂肪量增加,并导致系统及骨骼肌胰岛素抵抗形成,表现为60-120分钟的葡萄糖平均输注速率(30%,P<0.05)和骨骼肌葡萄糖摄取率(42%,P<0.05)明显下降；线粒体柠檬酸合酶活性下降；肌膜下和肌纤维间的线粒体复合体Ⅰ-Ⅳ活性下降20-40%(P<0.05),并且肌膜下的下降得更为明显。在肌膜下和肌纤维间的线粒体中,活性氧和丙二醛的水平在是明显升高的,而抗氧化酶活性是降低的。然而,口服SIRT1激动剂白藜芦醇能增加SIRT1活性、减少腹部脂肪,增加骨骼肌线粒体数量和改善胰岛素敏感性(43%,P<0.05)。白藜芦醇还能降低脂质过氧化反应和活性氧,恢复抗氧化酶的活性。
结论：本次实验表明了追赶生长可导致SIRT1表达及活性的降低,SIRT1激动剂白藜芦醇能增加SIRT1的表达及活性,通过增加骨骼肌线粒体复合体活性和加强抗氧化防御体系,来改善追赶生长大鼠的胰岛素敏感性。因此,SIRT1在大鼠腹部脂肪沉积、腹型肥胖胰岛素抵抗的形成中有重要的作用。
PART I:Three single nucleotide variants of SIRT1 gene are associated with overweight in a Chinese population
Objective:The prevalence of obesity and metabolic syndrome has fueled research on genetic loci of candidate genes. We herein aimed to explore whether common allelic variations in the SIRT1 gene were associated with overweight in a Chinese cohort.
Methods:Four haplotype-tagging single nucleotide polymorphisms (SNPs) were chosen for linkage disequilibrium, prevalence≥2.0%, minor allele frequency≥0.05, and coverage of the SIRT1 variability. They were genotyped in 820 Chinese individuals by PCR amplification and the ligase detection reaction.
Results:The rs1050929AA and rs10823116 GG alleles had significantly higher occurrence rates in the overweight group whereas the rs7894483TT alleles had a significantly lower rate. The association of carriers of rs10509291AT with modestly higher risk of overweight was consistent with a dominant model for the A allele. Carriers of two haplotypes, ATAA (rs7894483/rs10823116) and ATAG showed a significantly higher risk (OR:17.11 and 5.12) of overweight compared with carriers of AAAG (P<0.01). In agreement with a reduced risk of overweight in carriers of rs10509291TT genotype, carriers of TTATAA or TTATGG [rs10509291/rs7894483/rs10823116] had a lower risk of overweight than carriers of ATAA(OR:13.88 vs 17.11) and ATGG (OR:1.14 vs 5.12), respectively.
Conclusions:The findings of this study suggest that the rs10509291, rs7894483, and rs10823116 SNP alleles interact and have a significant association with excess weight gain in the Chinese population.
PARTⅡ:Resveratrol-activated SIRT1 Improves insulin resisitance in Catch-up Growth Rats
Objective:Caloric restriction (CR) followed by re-feeding, a phenomenon known as catch-up growth (CUG), affects mitochondrial function and results in systemic insulin resistance (IR). We intended to observe the effect of CUG on SIRTl expression and activity, and to increase SIRT1 activity, we interfered the rats with resveratrol, thus relieving the negative effects of mitochondrial dysfunction.
Methods:Rats (8 weeks of age) were divided into three groups:normal chow (NC), CUG, and catch-up growth with RES intervention (CUGE). Fat distribution, skeletal muscle and systemic IR were measured in each group after 4 and 8 weeks. Mitochondrial biogenesis and function, oxidative stress levels, and antioxidant enzyme activity in skeletal muscle were assessed.
Results:CUG induced IR resulted in significant reductions in both average glucose infusion rate60-120 (GIR60-120) at euglycemia and skeletal muscle glucose uptake. Mitochondrial citrate synthase (CS) activity was lower and activity of complexesⅠ-Ⅳin the intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondria were reduced by 20-40%, with the decrease being more pronounced in the SS fraction. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly higher in IMF and SS mitochondria while antioxidant enzyme activity was decreased. However, oral administration of RES increased SIRT1 activity, reduced abdominal fat accumulation, improved mitochondrial number and insulin sensitivity. RES treatment decreased levels of lipid peroxides and ROS, and restored antioxidant enzyme activity.
Conclusions:We investigated the potential of RES in CUG to prevent IR by increasing activity of the mitochondrial respiratory chain and antioxidant enzymes in skeletal muscle. This study demonstrates that SIRT1 protects insulin sensitivity by improving the activity of skeletal muscle mitochondrial complexes and the antioxidant defense status in CUG rats. Thus, SIRT1 has therapeutic potential for preventing CUG-related metabolic disorders.
引文
[1]Cheng MH. Asia-Pacific faces diabetes challenge. Lancet,2010,375(9733):2207-2210.
[2]Yoon KH, Lee JH, Kim JW, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet, 2006,368(9548):1681-1688.
[3]Wang J, Thornton JC, Russell M, et al. Asians have lower body mass index (BMI) but higher percent body fat than do whites:comparisons of anthropometric measurements. The American journal of clinical nutrition,1994,60(1):23-28.
[4]Obesity:preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser,2000,894:i-xii,1-253.
[5]Yang T, Fu M, Pestell R, et al. SIRT1 and endocrine signaling. Trends Endocrinol Metab,2006,17(5):186-191.
[6]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell, 2006,127(6):1109-1122.
[7]Crujeiras AB, Parra D, Goyenechea E, et al. Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur J Clin Invest, 2008,38(9):672-678.
[8]Pfluger PT, Herranz D, Velasco-Miguel S, et al. SIRT1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A,2008,105(28):9793-9798.
[9]van den Berg SW, Dolle ME, Imholz S, et al. Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes:a population-based cohort study. Int J Obes (Lond),2009,33(10):1143-1152.
[10]Zillikens MC, van Meurs JB, Rivadeneira F, et al. SIRT1 genetic variation is related to BMI and risk of obesity. Diabetes,2009,58(12):2828-2834.
[1]Li S, Zhao JH, Luan J, et al. Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies. Am J Clin Nutr,2010,91(1):184-190.
[2]Sasaki T, Kitamura T. Roles of FoxO1 and Sirtl in the central regulation of food intake. Endocr J,2010,57(11):939-946.
[3]Yang T, Fu M, Pestell R, et al. SIRT1 and endocrine signaling. Trends Endocrinol Metab,2006,17(5):186-191.
[4]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell, 2006,127(6):1109-1122.
[5]Crujeiras AB, Parra D, Goyenechea E, et al. Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur J Clin Invest, 2008,38(9):672-678.
[6]Imai S. SIRT1 and caloric restriction:an insight into possible trade-offs between robustness and frailty. Curr Opin Clin Nutr Metab Care,2009,12(4):350-356.
[7]Pfluger PT, Herranz D, Velasco-Miguel S, et al. Sirtl protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A,2008,105(28):9793-9798.
[8]Strum JC, Johnson JH, Ward J, et al. MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirTl. Mol Endocrinol, 2009,23(11):1876-1884.
[9]Peeters AV, Beckers S, Verrijken A, et al. Association of SIRT1 gene variation with visceral obesity. Hum Genet,2008,124(4):431-436.
[10]van den Berg SW, Dolle ME, Imholz S, et al. Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes:a population-based cohort study. Int J Obes (Lond),2009,33(10):1143-1152.
[11]Zillikens MC, van Meurs JB, Rivadeneira F, et al. SIRT1 genetic variation is related to BMI and risk of obesity. Diabetes,2009,58(12):2828-2834.
[12]Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States,1999-2004. JAMA,2006,295(13):1549-1555.
[13]Chen CM. Overview of obesity in Mainland China. Obes Rev,2008,9 Suppl 1:14-21.
[14]Prentice AM, Rayco-Solon P, Moore SE. Insights from the developing world: thrifty genotypes and thrifty phenotypes. Proc Nutr Soc,2005,64(2):153-161.
[15]Carlson CS, Eberle MA, Rieder MJ, et al. Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans. Nat Genet,2003,33(4):518-521.
[16]胡劲松,党娜娜,黄辰,et a1.国际人类基因组单体型图计划.国外医学(遗传学分册),2005,28(003)：129-132.
[17]The International HapMap Project. Nature,2003,426(6968):789-796.
[18]Picard F, Kurtev M, Chung N, et al. Sirtl promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature,2004,429(6993):771-776.
[19]Rutanen J, Yaluri N, Modi S, et al. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes,2010,59(4):829-835.
[20]Weyrich P, Machicao F, Reinhardt J, et al. SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention--the TULIP Study. BMC Med Genet,2008,9:100.
[21]Flachsbart F, Croucher PJ, Nikolaus S, et al. Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity. Exp Gerontol,2006,41(1):98-102.
[22]Feige JN, Lagouge M, Canto C, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab,2008,8(5):347-358.
[23]Alcain FJ, Villalba JM. Sirtuin activators. Expert Opin Ther Pat, 2009,19(4):403-414.
[24]Baur JA. Biochemical effects of SIRT1 activators. Biochim Biophys Acta, 2010,1804(8):1626-1634.
[25]Fischer-Posovszky P, Kukulus V, Tews D, et al. Resveratrol regulates human adipocyte number and function in a Sirtl-dependent manner. Am J Clin Nutr, 2010,92(1):5-15.
[26]Fullerton MD, Steinberg GR. SIRT1 takes a backseat to AMPK in the regulation of insulin sensitivity by resveratrol. Diabetes,2010,59(3):551-553.
[27]Cakir I, Perello M, Lansari 0, et al. Hypothalamic Sirtl regulates food intake in a rodent model system. PLoS One,2009,4(12):e8322.
[28]Holness MJ, Caton PW, Sugden MC. Acute and long-term nutrient-led modifications of gene expression:potential role of SIRT1 as a central co-ordinator of short and longer-term programming of tissue function. Nutrition,2010,26(5):491-501.
[29]Yoshizaki T, Schenk S, Imamura T, et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab, 2010,298(3):E419-428.
[30]Tontonoz P, Spiegelman BM. Fat and beyond:the diverse biology of PPARgamma. Annu Rev Biochem,2008,77:289-312.
[1]Morino K, Petersen KF, Dufour S et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 2005; 115:3587-93.
[2]Chen LL, Hu X, Zheng J et al. Lipid overaccumulation and drastic insulin resistance in adult catch-up growth rats induced by nutrition promotion after undernutrition. Metabolism 2011; 60:569-78.
[3]Lionetti L, Mollica MP, Crescenzo R et al. Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis. Int J Obes (Lond) 2007; 31:1596-604.
[4]Deng X, Cheng J, Zhang Y et al. Effects of caloric restriction on SIRT1 expression and apoptosis of islet beta cells in type 2 diabetic rats. Acta Diabetol 47:177-85.
[5]Crescenzo R, Lionetti L, Mollica MP et al. Altered skeletal muscle subsarcolemmal mitochondrial compartment during catch-up fat after caloric restriction. Diabetes 2006; 55:2286-93.
[6]Cettour-Rose P, Samec S, Russell AP et al. Redistribution of glucose from skeletal muscle to adipose tissue during catch-up fat:a link between catch-up growth and later metabolic syndrome. Diabetes 2005; 54:751-6.
[7]Petersen KF, Dufour S, Befroy D et al. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004; 350:664-71.
[8]Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005; 307:384-7.
[9]Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002; 51:2944-50.
[10]Lagouge M, Argmann C, Gerhart-Hines Z et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha. Cell 2006; 127:1109-22.
[11]Colom B, Oliver J, Roca P, Garcia-Palmer FJ. Caloric restriction and gender modulate cardiac muscle mitochondrial H2O2 production and oxidative damage. Cardiovasc Res 2007; 74:456-65.
[12]Kaeberlein M, Rabinovitch PS. Medicine:grapes versus gluttony. Nature 2006; 444:280-1.
[13]Kim CH, Kim MS, Youn JY et al. Lipolysis in skeletal muscle is decreased in high-fat-fed rats. Metabolism 2003; 52:1586-92.
[14]Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature 2006; 444:868-74.
[15]Scarpulla RC. Nuclear control of respiratory gene expression in mammalian cells. J Cell Biochem 2006; 97:673-83.
[16]Yoshizaki T, Milne JC, Imamura T et al. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol 2009; 29:1363-74.
[17]Zhang J. The direct involvement of SIRT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation. J Biol Chem 2007; 282:34356-64.
[18]Milne JC, Lambert PD, Schenk S et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007; 450:712-6.
[19]Aquilano K, Vigilanza P, Baldelli S et al. Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) and sirtuin 1 (SIRT1) reside in mitochondria: possible direct function in mitochondrial biogenesis. J Biol Chem 2010; 285:21590-9.
[20]Amat R, Planavila A, Chen SL et al. SIRT1 controls the transcription of the peroxisome proliferator-activated receptor-gamma Co-activator-1alpha (PGC-1alpha) gene in skeletal muscle through the PGC-1alpha autoregulatory loop and interaction with MyoD. J Biol Chem 2009; 284:21872-80.
[21]Nisoli E, Tonello C, Cardile A et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 2005; 310:314-7.
[22]Chen D, Bruno J, Easlon E et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev 2008; 22:1753-7.
[23]Civitarese AE, Carling S, Heilbronn LK et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007; 4:e76.
[24]Deng X, Cheng J, Zhang Y et al. Effects of caloric restriction on SIRT1 expression and apoptosis of islet beta cells in type 2 diabetic rats. Acta Diabetol 2009.
[25]Palmer JW, Tandler B, Hoppel CL. Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem 1977; 252:8731-9.
[26]Skulachev VP. A biochemical approach to the problem of aging:"megaproject" on membrane-penetrating ions. The first results and prospects. Biochemistry (Mosc) 2007; 72:1385-96.
[27]Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 2007; 292:C670-86.
[28]Guarente L. Mitochondria--a nexus for aging, calorie restriction, and sirtuins? Cell 2008; 132:171-6.
[29]Hawkins BJ, Levin MD, Doonan PJ et al. Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss. J Biol Chem 285:26494-505.
[30]Hasegawa K, Wakino S, Yoshioka K et al. Kidney-specific overexpression of SIRT1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem 2010; 285:13045-56.
[31]Morin C, Zini R, Albengres E et al. Evidence for resveratrol-induced preservation of brain mitochondria functions after hypoxia-reoxygenation. Drugs Exp Clin Res 2003; 29:227-33.
[32]陈璐璐,汪晓芬,郑涓et al.大鼠追赶生长早期脂肪组织和骨骼肌葡萄糖代谢差异及其机制.中华内分泌代谢杂志2008;24:4.
[33]Chen LL, Hu X, Zheng J et al. Lipid overaccumulation and drastic insulin resistance in adult catch-up growth rats induced by nutrition promotion after undernutrition. Metabolism 60:569-78.
[1]Sinclair DA, Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast. Cell.1997.91(7):1033-42.
[2]Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science.2000. 289(5487):2126-8.
[3]Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell.2001.107(2):137-48.
[4]Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science.2004.303(5666):2011-5.
[5]Picard F, Kurtev M, Chung N, et al. SIRT1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature.2004.429(6993):771-6.
[6]Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature.2005.434(7029):113-8.
[7]Moynihan KA, Grimm AA, Plueger MM, et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab.2005.2(2):105-17.
[8]Yang T, Fu M, Pestell R, Sauve AA. SIRT1 and endocrine signaling. Trends Endocrinol Metab.2006.17(5):186-91.
[9]Peeters AV, Beckers S, Verrijken A, et al. Association of SIRT1 gene variation with visceral obesity. Hum Genet.2008.124(4):431-6.
[10]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha. Cell.2006.127(6):1109-22.
[11]Zillikens MC, van MJB, Rivadeneira F, et al. SIRT1 genetic variation is related to BMI and risk of obesity. Diabetes.2009.58(12):2828-34.
[12]KENNEDY GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci.1953.140(901):578-96.
[13]Sasaki T, Kim HJ, Kobayashi M, et al. Induction of hypothalamic SIRT1 leads to cessation of feeding via agouti-related peptide. Endocrinology.2010.151(6): 2556-66.
[14]Satoh A, Brace CS, Ben-Josef G, et al. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J Neurosci.2010.30(30):10220-32.
[15]Ramadori G, Lee CE, Bookout AL, et al. Brain SIRT1:anatomical distribution and regulation by energy availability. J Neurosci.2008.28(40):9989-96.
[16]Ramadori G, Fujikawa T, Fukuda M, et al. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab.2010. 12(1):78-87.
[17]Lafontaine-Lacasse M, Richard D, Picard F. Effects of age and gender on Sirt 1 mRNA expressions in the hypothalamus of the mouse. Neurosci Lett.2010.480(1): 1-3.
[18]Herranz D, Munoz-Martin M, Canamero M, et al. SIRT1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun.2010.1:3.
[19]Tontonoz P, Spiegelman BM. Fat and beyond:the diverse biology of PPARgamma. Annu Rev Biochem.2008.77:289-312.
[20]Qiao L, Shao J. SIRT1 regulates adiponectin gene expression through Foxol-C/enhancer-binding protein alpha transcriptional complex. J Biol Chem. 2006.281(52):39915-24.
[21]Picard F, Kurtev M, Chung N, et al. SIRT1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature.2004.429(6993):771-6.
[22]Vaziri H, Dessain SK, Ng EE, et al. hSIR2(SIRTl) functions as an NAD-dependent p53 deacetylase. Cell.2001.107(2):149-59.
[23]Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem. 2005.280(16):16456-60.
[24]Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A.2007.104(31):12861-6.
[25]Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A.2007.104(31):12861-6.
[26]Erion DM, Yonemitsu S, Nie Y, et al. SIRT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Proc Natl Acad Sci U S A.2009.106(27):11288-93.
[27]Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab.2009.9(4):327-38.
[28]Heilbronn LK, Gan SK, Turner N, Campbell LV, Chisholm DJ. Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects. J Clin Endocrinol Metab.2007.92(4):1467-73.
[29]Gerhart-Hines Z, Rodgers JT, Bare O, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J.2007.26(7):1913-23.
[30]Liang F, Chen R, Nakagawa A, et al. Low-Frequency Electroacupuncture Improves Insulin Sensitivity in Obese Diabetic Mice through Activation of SIRT1/PGC-lalpha in Skeletal Muscle. Evid Based Complement Alternat Med. 2011.2011:735297.
[31]Sun C, Zhang F, Ge X, et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab.2007.6(4):307-19.
[32]Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance. Science.1993. 259(5091):87-91.
[33]Vaziri H, Dessain SK, Ng EE, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell.2001.107(2):149-59.
[34]Yoshizaki T, Milne JC, Imamura T, et al. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol.2009.29(5):1363-74.
[35]Schenk S, Saberi M, Olefsky JM. Insulin sensitivity:modulation by nutrients and inflammation. J Clin Invest. 2008.118(9):2992-3002.
[36]Yoshizaki T, Schenk S, Imamura T, et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab. 2010.298(3):E419-28.
[37]Hevener AL, Olefsky JM, Reichart D, et al. Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest.2007.117(6):1658-69.
[38]Yoshizaki T, Schenk S, Imamura T, et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab. 2010.298(3):E419-28.
[2]Yoon KH, Lee JH, Kim JW, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet, 2006,368(9548):1681-1688.
[3]Wang J, Thornton JC, Russell M, et al. Asians have lower body mass index (BMI) but higher percent body fat than do whites:comparisons of anthropometric measurements. The American journal of clinical nutrition,1994,60(1):23-28.
[4]Obesity:preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser,2000,894:i-xii,1-253.
[5]Yang T, Fu M, Pestell R, et al. SIRT1 and endocrine signaling. Trends Endocrinol Metab,2006,17(5):186-191.
[6]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell, 2006,127(6):1109-1122.
[7]Crujeiras AB, Parra D, Goyenechea E, et al. Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur J Clin Invest, 2008,38(9):672-678.
[8]Pfluger PT, Herranz D, Velasco-Miguel S, et al. SIRT1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A,2008,105(28):9793-9798.
[9]van den Berg SW, Dolle ME, Imholz S, et al. Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes:a population-based cohort study. Int J Obes (Lond),2009,33(10):1143-1152.
[10]Zillikens MC, van Meurs JB, Rivadeneira F, et al. SIRT1 genetic variation is related to BMI and risk of obesity. Diabetes,2009,58(12):2828-2834.
[1]Li S, Zhao JH, Luan J, et al. Cumulative effects and predictive value of common obesity-susceptibility variants identified by genome-wide association studies. Am J Clin Nutr,2010,91(1):184-190.
[2]Sasaki T, Kitamura T. Roles of FoxO1 and Sirtl in the central regulation of food intake. Endocr J,2010,57(11):939-946.
[3]Yang T, Fu M, Pestell R, et al. SIRT1 and endocrine signaling. Trends Endocrinol Metab,2006,17(5):186-191.
[4]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell, 2006,127(6):1109-1122.
[5]Crujeiras AB, Parra D, Goyenechea E, et al. Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur J Clin Invest, 2008,38(9):672-678.
[6]Imai S. SIRT1 and caloric restriction:an insight into possible trade-offs between robustness and frailty. Curr Opin Clin Nutr Metab Care,2009,12(4):350-356.
[7]Pfluger PT, Herranz D, Velasco-Miguel S, et al. Sirtl protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A,2008,105(28):9793-9798.
[8]Strum JC, Johnson JH, Ward J, et al. MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirTl. Mol Endocrinol, 2009,23(11):1876-1884.
[9]Peeters AV, Beckers S, Verrijken A, et al. Association of SIRT1 gene variation with visceral obesity. Hum Genet,2008,124(4):431-436.
[10]van den Berg SW, Dolle ME, Imholz S, et al. Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes:a population-based cohort study. Int J Obes (Lond),2009,33(10):1143-1152.
[11]Zillikens MC, van Meurs JB, Rivadeneira F, et al. SIRT1 genetic variation is related to BMI and risk of obesity. Diabetes,2009,58(12):2828-2834.
[12]Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States,1999-2004. JAMA,2006,295(13):1549-1555.
[13]Chen CM. Overview of obesity in Mainland China. Obes Rev,2008,9 Suppl 1:14-21.
[14]Prentice AM, Rayco-Solon P, Moore SE. Insights from the developing world: thrifty genotypes and thrifty phenotypes. Proc Nutr Soc,2005,64(2):153-161.
[15]Carlson CS, Eberle MA, Rieder MJ, et al. Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans. Nat Genet,2003,33(4):518-521.
[16]胡劲松,党娜娜,黄辰,et a1.国际人类基因组单体型图计划.国外医学(遗传学分册),2005,28(003)：129-132.
[17]The International HapMap Project. Nature,2003,426(6968):789-796.
[18]Picard F, Kurtev M, Chung N, et al. Sirtl promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature,2004,429(6993):771-776.
[19]Rutanen J, Yaluri N, Modi S, et al. SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes,2010,59(4):829-835.
[20]Weyrich P, Machicao F, Reinhardt J, et al. SIRT1 genetic variants associate with the metabolic response of Caucasians to a controlled lifestyle intervention--the TULIP Study. BMC Med Genet,2008,9:100.
[21]Flachsbart F, Croucher PJ, Nikolaus S, et al. Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity. Exp Gerontol,2006,41(1):98-102.
[22]Feige JN, Lagouge M, Canto C, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab,2008,8(5):347-358.
[23]Alcain FJ, Villalba JM. Sirtuin activators. Expert Opin Ther Pat, 2009,19(4):403-414.
[24]Baur JA. Biochemical effects of SIRT1 activators. Biochim Biophys Acta, 2010,1804(8):1626-1634.
[25]Fischer-Posovszky P, Kukulus V, Tews D, et al. Resveratrol regulates human adipocyte number and function in a Sirtl-dependent manner. Am J Clin Nutr, 2010,92(1):5-15.
[26]Fullerton MD, Steinberg GR. SIRT1 takes a backseat to AMPK in the regulation of insulin sensitivity by resveratrol. Diabetes,2010,59(3):551-553.
[27]Cakir I, Perello M, Lansari 0, et al. Hypothalamic Sirtl regulates food intake in a rodent model system. PLoS One,2009,4(12):e8322.
[28]Holness MJ, Caton PW, Sugden MC. Acute and long-term nutrient-led modifications of gene expression:potential role of SIRT1 as a central co-ordinator of short and longer-term programming of tissue function. Nutrition,2010,26(5):491-501.
[29]Yoshizaki T, Schenk S, Imamura T, et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab, 2010,298(3):E419-428.
[30]Tontonoz P, Spiegelman BM. Fat and beyond:the diverse biology of PPARgamma. Annu Rev Biochem,2008,77:289-312.
[1]Morino K, Petersen KF, Dufour S et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest 2005; 115:3587-93.
[2]Chen LL, Hu X, Zheng J et al. Lipid overaccumulation and drastic insulin resistance in adult catch-up growth rats induced by nutrition promotion after undernutrition. Metabolism 2011; 60:569-78.
[3]Lionetti L, Mollica MP, Crescenzo R et al. Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis. Int J Obes (Lond) 2007; 31:1596-604.
[4]Deng X, Cheng J, Zhang Y et al. Effects of caloric restriction on SIRT1 expression and apoptosis of islet beta cells in type 2 diabetic rats. Acta Diabetol 47:177-85.
[5]Crescenzo R, Lionetti L, Mollica MP et al. Altered skeletal muscle subsarcolemmal mitochondrial compartment during catch-up fat after caloric restriction. Diabetes 2006; 55:2286-93.
[6]Cettour-Rose P, Samec S, Russell AP et al. Redistribution of glucose from skeletal muscle to adipose tissue during catch-up fat:a link between catch-up growth and later metabolic syndrome. Diabetes 2005; 54:751-6.
[7]Petersen KF, Dufour S, Befroy D et al. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 2004; 350:664-71.
[8]Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005; 307:384-7.
[9]Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002; 51:2944-50.
[10]Lagouge M, Argmann C, Gerhart-Hines Z et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha. Cell 2006; 127:1109-22.
[11]Colom B, Oliver J, Roca P, Garcia-Palmer FJ. Caloric restriction and gender modulate cardiac muscle mitochondrial H2O2 production and oxidative damage. Cardiovasc Res 2007; 74:456-65.
[12]Kaeberlein M, Rabinovitch PS. Medicine:grapes versus gluttony. Nature 2006; 444:280-1.
[13]Kim CH, Kim MS, Youn JY et al. Lipolysis in skeletal muscle is decreased in high-fat-fed rats. Metabolism 2003; 52:1586-92.
[14]Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature 2006; 444:868-74.
[15]Scarpulla RC. Nuclear control of respiratory gene expression in mammalian cells. J Cell Biochem 2006; 97:673-83.
[16]Yoshizaki T, Milne JC, Imamura T et al. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol 2009; 29:1363-74.
[17]Zhang J. The direct involvement of SIRT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation. J Biol Chem 2007; 282:34356-64.
[18]Milne JC, Lambert PD, Schenk S et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007; 450:712-6.
[19]Aquilano K, Vigilanza P, Baldelli S et al. Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) and sirtuin 1 (SIRT1) reside in mitochondria: possible direct function in mitochondrial biogenesis. J Biol Chem 2010; 285:21590-9.
[20]Amat R, Planavila A, Chen SL et al. SIRT1 controls the transcription of the peroxisome proliferator-activated receptor-gamma Co-activator-1alpha (PGC-1alpha) gene in skeletal muscle through the PGC-1alpha autoregulatory loop and interaction with MyoD. J Biol Chem 2009; 284:21872-80.
[21]Nisoli E, Tonello C, Cardile A et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 2005; 310:314-7.
[22]Chen D, Bruno J, Easlon E et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev 2008; 22:1753-7.
[23]Civitarese AE, Carling S, Heilbronn LK et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007; 4:e76.
[24]Deng X, Cheng J, Zhang Y et al. Effects of caloric restriction on SIRT1 expression and apoptosis of islet beta cells in type 2 diabetic rats. Acta Diabetol 2009.
[25]Palmer JW, Tandler B, Hoppel CL. Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem 1977; 252:8731-9.
[26]Skulachev VP. A biochemical approach to the problem of aging:"megaproject" on membrane-penetrating ions. The first results and prospects. Biochemistry (Mosc) 2007; 72:1385-96.
[27]Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 2007; 292:C670-86.
[28]Guarente L. Mitochondria--a nexus for aging, calorie restriction, and sirtuins? Cell 2008; 132:171-6.
[29]Hawkins BJ, Levin MD, Doonan PJ et al. Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss. J Biol Chem 285:26494-505.
[30]Hasegawa K, Wakino S, Yoshioka K et al. Kidney-specific overexpression of SIRT1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem 2010; 285:13045-56.
[31]Morin C, Zini R, Albengres E et al. Evidence for resveratrol-induced preservation of brain mitochondria functions after hypoxia-reoxygenation. Drugs Exp Clin Res 2003; 29:227-33.
[32]陈璐璐,汪晓芬,郑涓et al.大鼠追赶生长早期脂肪组织和骨骼肌葡萄糖代谢差异及其机制.中华内分泌代谢杂志2008;24:4.
[33]Chen LL, Hu X, Zheng J et al. Lipid overaccumulation and drastic insulin resistance in adult catch-up growth rats induced by nutrition promotion after undernutrition. Metabolism 60:569-78.
[1]Sinclair DA, Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast. Cell.1997.91(7):1033-42.
[2]Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science.2000. 289(5487):2126-8.
[3]Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell.2001.107(2):137-48.
[4]Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science.2004.303(5666):2011-5.
[5]Picard F, Kurtev M, Chung N, et al. SIRT1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature.2004.429(6993):771-6.
[6]Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature.2005.434(7029):113-8.
[7]Moynihan KA, Grimm AA, Plueger MM, et al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab.2005.2(2):105-17.
[8]Yang T, Fu M, Pestell R, Sauve AA. SIRT1 and endocrine signaling. Trends Endocrinol Metab.2006.17(5):186-91.
[9]Peeters AV, Beckers S, Verrijken A, et al. Association of SIRT1 gene variation with visceral obesity. Hum Genet.2008.124(4):431-6.
[10]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-lalpha. Cell.2006.127(6):1109-22.
[11]Zillikens MC, van MJB, Rivadeneira F, et al. SIRT1 genetic variation is related to BMI and risk of obesity. Diabetes.2009.58(12):2828-34.
[12]KENNEDY GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci.1953.140(901):578-96.
[13]Sasaki T, Kim HJ, Kobayashi M, et al. Induction of hypothalamic SIRT1 leads to cessation of feeding via agouti-related peptide. Endocrinology.2010.151(6): 2556-66.
[14]Satoh A, Brace CS, Ben-Josef G, et al. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J Neurosci.2010.30(30):10220-32.
[15]Ramadori G, Lee CE, Bookout AL, et al. Brain SIRT1:anatomical distribution and regulation by energy availability. J Neurosci.2008.28(40):9989-96.
[16]Ramadori G, Fujikawa T, Fukuda M, et al. SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab.2010. 12(1):78-87.
[17]Lafontaine-Lacasse M, Richard D, Picard F. Effects of age and gender on Sirt 1 mRNA expressions in the hypothalamus of the mouse. Neurosci Lett.2010.480(1): 1-3.
[18]Herranz D, Munoz-Martin M, Canamero M, et al. SIRT1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun.2010.1:3.
[19]Tontonoz P, Spiegelman BM. Fat and beyond:the diverse biology of PPARgamma. Annu Rev Biochem.2008.77:289-312.
[20]Qiao L, Shao J. SIRT1 regulates adiponectin gene expression through Foxol-C/enhancer-binding protein alpha transcriptional complex. J Biol Chem. 2006.281(52):39915-24.
[21]Picard F, Kurtev M, Chung N, et al. SIRT1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature.2004.429(6993):771-6.
[22]Vaziri H, Dessain SK, Ng EE, et al. hSIR2(SIRTl) functions as an NAD-dependent p53 deacetylase. Cell.2001.107(2):149-59.
[23]Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}. J Biol Chem. 2005.280(16):16456-60.
[24]Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A.2007.104(31):12861-6.
[25]Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A.2007.104(31):12861-6.
[26]Erion DM, Yonemitsu S, Nie Y, et al. SIRT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Proc Natl Acad Sci U S A.2009.106(27):11288-93.
[27]Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab.2009.9(4):327-38.
[28]Heilbronn LK, Gan SK, Turner N, Campbell LV, Chisholm DJ. Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects. J Clin Endocrinol Metab.2007.92(4):1467-73.
[29]Gerhart-Hines Z, Rodgers JT, Bare O, et al. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J.2007.26(7):1913-23.
[30]Liang F, Chen R, Nakagawa A, et al. Low-Frequency Electroacupuncture Improves Insulin Sensitivity in Obese Diabetic Mice through Activation of SIRT1/PGC-lalpha in Skeletal Muscle. Evid Based Complement Alternat Med. 2011.2011:735297.
[31]Sun C, Zhang F, Ge X, et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab.2007.6(4):307-19.
[32]Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance. Science.1993. 259(5091):87-91.
[33]Vaziri H, Dessain SK, Ng EE, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell.2001.107(2):149-59.
[34]Yoshizaki T, Milne JC, Imamura T, et al. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol.2009.29(5):1363-74.
[35]Schenk S, Saberi M, Olefsky JM. Insulin sensitivity:modulation by nutrients and inflammation. J Clin Invest. 2008.118(9):2992-3002.
[36]Yoshizaki T, Schenk S, Imamura T, et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab. 2010.298(3):E419-28.
[37]Hevener AL, Olefsky JM, Reichart D, et al. Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest.2007.117(6):1658-69.
[38]Yoshizaki T, Schenk S, Imamura T, et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab. 2010.298(3):E419-28.