臺灣博碩士論文加值系統

Sirtuin 1，又稱之為SIRT1，是屬於Sirtuin哺乳動物蛋白質家族成員之一。SIRT1與其非脊椎動物同源蛋白Sir2 (silent information regulator 2 gene) 皆為菸鹼醯胺腺嘌呤二核苷酸依賴型去乙醯酵素，以菸鹼醯胺腺嘌呤二核苷酸 (NAD+) 與蛋白質上乙醯態之離胺酸為受質，進行去乙醯化作用。先前研究發現，此二種酵素都可因低能量情況或能量限制時而增加其表現量。後續其他研究發現，哺乳動物之SIRT1可以藉由調控其目標蛋白而改變身體代謝、神經及免疫功能，進而產生抗老化與延長壽命之效果。本研究目的在於了解不同代謝能濃度對於豬隻組織中SIRT1及其相關基因表現之影響，並探討高脂飼糧下對於豬隻與小鼠體內SIRT1與能量代謝之影響。
在試驗第一部分，使用十週齡蘭嶼豬進行十週的營養試驗，於期間分別餵飼每公斤2500 (L) 、2700 (M) 及2900 (H) 大卡之飼糧。結果顯示，三組間體重、飼料轉換率及平均日增重皆無差異。而L組別血液中具有較高之三酸甘油酯、高密度脂蛋白及血糖，並且在肝臟中發現其具有較高之SIRT1與脂質合成基因表現。L組別肝臟中合成較多三酸甘油酯，並在血液中觀察到具有較高的血脂現象，於此推斷其具有較高的能量利用效率。另一部分，使用五月齡蘭嶼豬進行六個月的營養試驗，於期間分別餵飼每公斤2700 (CON) 與3700 (HFD) 大卡之飼糧。結果顯示，HFD組具有較高的體重與背脂厚度，但試驗後兩組血脂分析則無出現差異。同時在肝臟中發現HFD組別具有較高的SIRT1與脂質分解基因表現，其餘基因表現皆無差異。據此推斷SIRT1在HFD餵飼下具有避免肥胖造成傷害之功能。
為了更加確定SIRT1是否可以保護身體在肥胖初期避免肥胖飼糧下造成之代謝傷害。此部分利用七週齡小鼠飼食一般飼糧 (CON) 與肥胖飼糧 (HFD) 探討各時期的結果。結果顯示，在試驗初期 (兩週) 肝臟中SIRT1於HFD組有增加的現象，但在長期間餵飼之下則沒有顯著差異，然而在年紀較大之動物上發現SIRT1有增加的現象。體重與血脂分析部分，在第二週時便可發現體重、三酸甘油酯、總膽固醇與血糖皆有顯著提升的效果。於此試驗推論，SIRT1可能在肥胖初期扮演保護的角色，隨著年紀增加其作用活性降低或無法抵禦老化造成之影響，因此仍然出現老化與肥胖現象。
綜觀上述，本研究指出豬隻肝臟中SIRT1表現在能量限制的情況下增加，此點與其他物種具有相同的結果。高能量飼糧餵飼兩週，小鼠肝臟中SIRT1也有提升的現象，在此推斷，SIRT1在肥胖初期具有保護的效果。然而，延長餵飼時間SIRT1的功效則失去保護，其相關機制有待進一步釐清。

Sirtuin 1, also called SIRT1, is one member of sirtuin family proteins in mammals. SIRT1 and its invertebrate homologue, silencing information regulator 2 (Sir2), both are nicotinamide adenine dinucleotide (NAD+) -dependent enzymes that exert deacetylating action on acetyl-Lysine of proteins. Previous studies showed that SIRT1 and Sir2 were up-regulated under low energy conditions or calorie restriction (CR). Furthermore, increasing SIRT1 expression regulated its target proteins to modulate metabolic, neuronal and immunological functions, and therefore lead to anti-aging and longevity. This study was focused on the link between metabolic energy (ME) level and related gene expressions SIRT1 in various tissues of swine, and in mouse models in response to high fat diet (HFD).
In the first part of this study, 10-week-old Lanyu miniature pigs were fed with diet with various ME levels (2500 (L), 2700 (M) or 2900 (H) kcal/kg) for 10 weeks. There was no difference on body weight, feed conversion ratio and average daily gain among three groups. L group had a higher plasma level of triglyceride (TG), high density high density lipoprotein (HDL) and glucose than H group. Increased mRNA expression of SIRT1 and lipogenic genes were found in liver of L group. And hepatic triglyceride content was no different among three groups. These results suggested that low energy diet induced high efficiency by SIRT1, and fluxed to peripheral tissues for further use. In the second part of this study, 5-month-old Lanyu miniature pigs were fed with control (CON) or HFD, as 2700 or 3700 (HFD) kcal ME/kg, for 6-month period. HFD pigs had a higher body weight and backfat thickness, but no difference in blood parameters, including TG, total cholesterol, HDL and LDL level between two groups was observed. After 6 month experiment period, Lanyu pig was not induced obesity. HFD pigs had an increase in hepatic transcript and protein levels of SIRT1 and lipolytic genes, suggesting a protective role of SIRT1 in HFD-induced metabolic damage of porcine model.
In order to elucidate whether SIRT1 protects mice from HFD-induced metabolic damages in early stage of obesity, the third experiment was designed using 7-week-old mice as an animal model in response to high fat diet (HFD) for various duration. Results showed that SIRT1 mRNA expression increased with advancing age. Compared with CON mice, HFD mice had higher hepatic SIRT1 mRNA expression at 2-week period, while there was no difference after 25-week feeding. In addition, body weight, plasma TG, total cholesterol and glucose level were elevated since 2 week by HFD. These results suggested that SIRT1 might play a protective role in early obesity stage, and its activity and protection decline with advancing age.
Taken together, this study indicated that porcine hepatic SIRT1 expression was induced in CR as well as the rodent model. While in the high energy status induced by HFD-feeding 2 weeks, the hepatic SIRT1 expression of mice was elevated as well. These results suggest a protective role of SIRT1 in early obesity stage. However, the related mechanism needs further elucidation.

謝誌 i
中文摘要 ii
Abstract iv
LIST OF FIGURES vii
LIST OF TABLES viii
LIST OF ABBREVIATIONS ix
Chapter 1: Introduction 1
I. Energy Intake 1
II. Obesity and Metabolic Syndrome 5
III. Sirtuin 1 (SIRT1) 10
Chapter 2: Materials and Methods 15
I. Experimental design and purpose 15
II. Animals and diets 15
III. Blood parameter analysis 16
IV. Sample and collection 17
V. Protein concentration 17
VI. Triglyceride content in tissue 18
VII. Oxygen radical absorbance capacity (ORAC)in tissue 18
VIII. Real-time quantitative polymerase chain reaction (PCR) analysis 19
IX. Protein expression and quantitation 21
X. Statistical analysis 22
Chapter 3: Results 34
I. ME vs. SIRT1 34
II. HFD in porcine model vs. SIRT1 41
III. HFD-feeding duration in mouse model vs. SIRT1 48
Chapter 4: Discussion 55
I. Low ME vs. SIRT1 55
II. HFD vs. SIRT1 56
III. Age vs. SIRT1 57
References 59

Abate N, Garg A, Peshock R, Stray-Gundersen J, Grundy S. 1995. Relationships of generalized and regional adiposity to insulin sensitivity in men. Journal of Clinical Investigation 96: 88-98.
Abbasi F, Brown BW, Lamendola C, McLaughlin T, Reaven GM. 2002. Relationship between obesity, insulin resistance, and coronary heart disease risk. Journal of the American College of Cardiology 40: 937-943.
Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner SF, Sadoshima J. 2007. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circulation Research 100: 1512-1521.
Apel K, Hirt H. 2004. Reactive oxygen species: metabolism, oxidative stress, and signal transduction. Annual Review of Plant Biology 55: 373-399.
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K. 1999. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochemical and Biophysical Research Communications 257: 79-83.
Balaban RS, Nemoto S, Finkel T. 2005. Mitochondria, oxidants, and aging. Cell 120: 483-495.
Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE. 2004. Regulation of fasted blood glucose by resistin. Science''s STKE 303: 1195-1198.
Banks AS, Kon N, Knight C, Matsumoto M, Gutiérrez-Juárez R, Rossetti L, Gu W, Accili D. 2008. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metabolism 8: 333-341.
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K. 2006. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444: 337-342.
Bergman RN, Kim SP, Catalano KJ, Hsu IR, Chiu JD, Kabir M, Hucking K, Ader M. 2006. Why visceral fat is bad: mechanisms of the metabolic syndrome. Obesity 14: 16S-19S.
Bevilacqua L, Ramsey JJ, Hagopian K, Weindruch R, Harper ME. 2004. Effects of short-and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production. American Journal of Physiology - Endocrinology and Metabolism 286: E852-E861.
Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA. 2002. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. Journal of Biological Chemistry 277: 45099-45170.
Blüher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, Kahn CR. 2002. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Developmental Cell 3: 25-38.
Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, McDonagh T, Lemieux M, McBurney M, Szilvasi A. 2005. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells. PLoS biology 4: e31.
Brownlee M. 2001. Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813-820.
Cadenas E. 1989. Biochemistry of oxygen toxicity. Annual Review of Biochemistry 58: 79-110.
Campbell R, Dunkin A. 1983. The effects of energy intake and dietary protein on nitrogen retention, growth performance, body composition and some aspects of energy metabolism of baby pigs. British Journal of Nutrition 49: 221-230.
Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. 2009. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458: 1056-1060.
Cantó C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J. 2010. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metabolism 11: 213-219.
Carr MC, Brunzell JD. 2004. Abdominal obesity and dyslipidemia in the metabolic syndrome: importance of type 2 diabetes and familial combined hyperlipidemia in coronary artery disease risk. Journal of Clinical Endocrinology and Metabolism 89: 2601-2607.
Chen D, Bruno J, Easlon E, Lin SJ, Cheng HL, Alt FW, Guarente L. 2008. Tissue-specific regulation of SIRT1 by calorie restriction. Genes and Development 22: 1753-1757.
Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E. 2007. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Medicine 4: e76.
Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. 2004. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305: 390-392.
Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW. 2009. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325: 201-204.
Coste A, Louet JF, Lagouge M, Lerin C, Antal MC, Meziane H, Schoonjans K, Puigserver P, O''Malley BW, Auwerx J. 2008. The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α. Proceedings of the National Academy of Sciences 105: 17187-17192.
Da Poian A, El-Bacha T, Luz M. 2010. Nutrient utilization in humans: metabolism pathways. Nature Education 3: 11.
Després JP, Lemieux I. 2006. Abdominal obesity and metabolic syndrome. Nature 444: 881-887.
Despres JP, Moorjani S, Lupien PJ, Tremblay A, Nadeau A, Bouchard C. 1990. Regional distribution of body fat, plasma lipoproteins, and cardiovascular disease. Arteriosclerosis Thrombosis and Vascular Biology 10: 497-511.
Després JP. 2006. Abdominal obesity: the most prevalent cause of the metabolic syndrome and related cardiometabolic risk. European Heart Journal Supplements 8: B4-B12.
Dyson MC, Alloosh M, Vuchetich JP, Mokelke EA, Sturek M. 2006. Components of metabolic syndrome and coronary artery disease in female Ossabaw swine fed excess atherogenic diet. Comparative Medicine 56: 35-45.
Escande C, Chini CCS, Nin V, Dykhouse KM, Novak CM, Levine J, Van Deursen J, Gores GJ, Chen J, Lou Z. 2010. Deleted in breast cancer–1 regulates SIRT1 activity and contributes to high-fat diet–induced liver steatosis in mice. Journal of Clinical Investigation 120: 545-558.
Evans DJ, Hoffman RG, Kalkhoff RK, Kissebah AH. 1984. Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women. Metabolism 33: 68-75.
Ferrara N, Rinaldi B, Corbi G, Conti V, Stiuso P, Boccuti S, Rengo G, Rossi F, Filippelli A. 2008. Exercise training promotes SIRT1 activity in aged rats. Rejuvenation Research 11: 139-150.
Fielding CJ, Fielding P. 1995. Molecular physiology of reverse cholesterol transport. Journal of Lipid Research 36: 211-228.
Freedland ES. 2004. Role of a critical visceral adipose tissue threshold (CVATT) in metabolic syndrome: implications for controlling dietary carbohydrates: a review. Nutrition and Metabolism 1: 12.
Frescas D, Valenti L, Accili D. 2005. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. Journal of Biological Chemistry 280: 20589-20595.
Friedman JM, Halaas JL. 1998. Leptin and the regulation of body weight in mammals. Nature 395: 763-770.
Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. 2004. Increased oxidative stress in obesity and its impact on metabolic syndrome. Journal of Clinical Investigation 114: 1752-1761.
Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P. 2007. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α. The EMBO Journal 26: 1913-1923.
Giannakou ME, Partridge L. 2004. The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends in Cell Biology 14: 408-412.
Goodpaster B, Thaete F, Simoneau J, Kelley D. 1997. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes 46: 1579-1585.
Guarente L. 2005. Calorie restriction--the SIR2 connection. Cell 120: 473-482.
Do GM, Kwon EY, Kim HJ, Jeon SM, Ha TY, Park T, Choi MS. 2008. Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice. Biochemical and Biophysical Research Communications 374:55-59.
Halliwell B, Gutteridge JMC. 2007. Free radicals in biology and medicine. Free Radical Biology and Medicine 10: 449-450.
Han L, Zhou R, Niu J, McNutt MA, Wang P, Tong T. 2010. SIRT1 is regulated by a PPARγ–SIRT1 negative feedback loop associated with senescence. Nucleic Acids Research 38: 7458-7471.
Harman D. 1983. Free radical theory of aging: consequences of mitochondrial aging. Age 6: 86-94.
Harper JM, Leathers CW, Austad SN. 2006. Does caloric restriction extend life in wild mice? Aging Cell 5: 441-449.
Havel R. 1984. The formation of LDL: mechanisms and regulation. Journal of Lipid Research 25: 1570-1576.
Hayashida S, Arimoto A, Kuramoto Y, Kozako T, Honda S, Shimeno H, Soeda S. 2010. Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of PPARα in mice. Molecular and Cellular Biochemistry 339: 285-292.
Houtkooper RH, Pirinen E, Auwerx J. 2012. Sirtuins as regulators of metabolism and healthspan. Nature Reviews Molecular Cell Biology 13: 225-238.
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL. 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: 191-196.
Ibrahim MM. 2010. Subcutaneous and visceral adipose tissue: structural and functional differences. Obesity Reviews 11: 11-18.
Imai S, Armstrong CM, Kaeberlein M, Guarente L. 2000. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403: 795-799.
Imai S. 2009. The NAD World: a new systemic regulatory network for metabolism and aging-Sirt1, systemic NAD biosynthesis, and their importance. Cell Biochemistry and Biophysics 53: 65-74.
Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M. 2000. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD (P) H oxidase in cultured vascular cells. Diabetes 49: 1939-1945.
Isomaa B, Almgren P, Tuomi T, Forsén B, Lahti K, Nissén M, Taskinen MR, Groop L. 2001. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24: 683-689.
Johansen T, Hansen HS, Richelsen B, Malmlof K. 2001. The obese Gottingen minipig as a model of the metabolic syndrome: dietary effects on obesity, insulin sensitivity, and growth hormone profile. Comparative Medicine 51: 150-155.
Kaeberlein M, McVey M, Guarente L. 1999. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes and Development 13: 2570-2580.
Kamari Y, Shaish A, Vax E, Shemesh S, Kandel-Kfir M, Arbel Y, Olteanu S, Barshack I, Dotan S, Voronov E. 2011. Lack of interleukin-1 [alpha] or interleukin-1 [beta] inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Journal of Hepatology 55: 1086-1094.
Kilyn E. 1923. Studien ueber das hypertonie-hyperglykamie-hyperurikamie syndrome. Zentralblatt für Innere Medizin 44: 105-127.
Kim EJ, Kho JH, Kang MR, Um SJ. 2007. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Molecular Cell 28: 277-290.
Kim J, Tchernyshyov I, Semenza GL, Dang CV. 2006. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism 3: 177-185.
Kobayashi K, Inoguchi T. 2005. Adipokines: therapeutic targets for metabolic syndrome. Current Drug Targets 6: 525-529.
Lafontan M. 2005. Fat cells: afferent and efferent messages define new approaches to treat obesity. Annual Review of Pharmacology and Toxicology 45: 119-146.
Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. 2002. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. Journal of the American Medical Association 288: 2709-2716.
Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L, Sternglanz R. 2000. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proceedings of the National Academy of Sciences 97: 5807-5811.
Lau DCW, Dhillon B, Yan H, Szmitko PE, Verma S. 2005. Adipokines: molecular links between obesity and atheroslcerosis. American Journal of Physiology - Heart and Circulatory Physiology 288: H2031-H2041.
Lebovitz HE, Banerji MA. 2005. Point: visceral adiposity is causally related to insulin resistance. Diabetes Care 28: 2322-2325.
Lewis G, Uffelman K, Szeto L, Steiner G. 1993. Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals. Diabetes 42: 833-842.
Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. 1995. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. Journal of Clinical Investigation 95: 158-166.
Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L. 2007. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Molecular Cell 28: 91-106.
Lin SJ, Defossez PA, Guarente L. 2000. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289: 2126-2128.
Lin SJ, Ford E, Haigis M, Liszt G, Guarente L. 2004. Calorie restriction extends yeast life span by lowering the level of NADH. Genes and Development 18: 12-16.
Marieb EN, Hoehn K. 2008. Anatomy and Physiology. Benjamin Cummings.
Mårin P, Andersson B, Ottosson M, Olbe L, Chowdhury B, Kvist H, Holm G, Sjöström L, Björntorp P. 1992. The morphology and metabolism of intraabdominal adipose tissue in men. Metabolism 41: 1242-1248.
Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. 2004. Adiponectin and metabolic syndrome. Arteriosclerosis Thrombosis and Vascular Biology 24: 29-33.
McCay CM, Crowell MF, Maynard L. 1935. The effect of retarded growth upon the length of life span and upon the ultimate body size. Journal of Nutrition 10: 63-79.
Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB. 2007. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450: 712-716.
Mohamed-Ali V, Goodrick S, Rawesh A, Katz D, Miles J, Yudkin J, Klein S, Coppack S. 1997. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. Journal of Clinical Endocrinology and Metabolism 82: 4196-4200.
Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Méneur C, Permutt MA, Imai S. 2005. Increased dosage of mammalian Sir2 in pancreatic [beta] cells enhances glucose-stimulated insulin secretion in mice. Cell Metabolism 2: 105-117.
Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, Toiber D, Kulkarni M, Wang Q, Najafi-Shoushtari SH. 2011. A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development. Molecular Cell 42: 689-699.
Neeb ZP, Edwards JM, Alloosh M, Long X, Mokelke EA, Sturek M. 2010. Metabolic syndrome and coronary artery disease in Ossabaw compared with Yucatan swine. Comparative Medicine 60: 300-315.
Nemoto S, Fergusson MM, Finkel T. 2004. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 306: 2105-2018.
Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E. 2005. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science''s STKE 310: 314-317.
Noriega LG, Feige JN, Canto C, Yamamoto H, Yu J, Herman MA, Mataki C, Kahn BB, Auwerx J. 2011. CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability. EMBO reports 12: 1069-1076.
Park KG, Park KS, Kim MJ, Kim HS, Suh YS, Ahn JD, Park KK, Chang YC, Lee IK. 2004. Relationship between serum adiponectin and leptin concentrations and body fat distribution. Diabetes Research and Clinical Practice 63: 135-142.
Partridge L, Piper MDW, Mair W. 2005. Dietary restriction in Drosophila. Mechanisms of Ageing and Development 126: 938-950.
Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E. 2008. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metabolism 8: 157-168.
Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschöp MH. 2008. Sirt1 protects against high-fat diet-induced metabolic damage. Proceedings of the National Academy of Sciences 105: 9793-9798.
Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, De Oliveira RM, Leid M, McBurney MW, Guarente L. 2004. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 429: 771-776.
Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, Wu SY, Chiang CM, Veenstra TD, Kemper JK. 2010. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. Journal of Biological Chemistry 285: 33959-33970.
Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. 2009. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metabolism 9: 327-338.
Ramadori G, Lee CE, Bookout AL, Lee S, Williams KW, Anderson J, Elmquist JK, Coppari R. 2008. Brain SIRT1: anatomical distribution and regulation by energy availability. Journal of Neuroscience 28: 9989-9996.
Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. 2005. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434: 113-118.
Rogina B, Helfand SL. 2004. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proceedings of the National Academy of Sciences 101: 15998-16003.
Seo J, Fortuno III ES, Suh JM, Stenesen D, Tang W, Parks EJ, Adams CM, Townes T, Graff JM. 2009. Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes 58: 2565-2573.
Shimomura I, Funahasm T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K. 1996. Enhanced expression of PAI–1 in visceral fat: possible contributor to vascular disease in obeisty. Nature Medicine 2: 800-803.
Smith JS, Brachmann CB, Celic I, Kenna MA, Muhammad S, Starai VJ, Avalos JL, Escalante-Semerena JC, Grubmeyer C, Wolberger C. 2000. A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proceedings of the National Academy of Sciences 97: 6658-6663.
Sohal RS, Weindruch R. 1996. Oxidative stress, caloric restriction, and aging. Science 273: 59-63.
Steinberg D. 1997. Low density lipoprotein oxidation and its pathobiological significance. Journal of Biological Chemistry 272: 20963-20966.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee R, Wright CM, Patel HR, Ahima RS, Lazar MA. 2001. The hormone resistin links obesity to diabetes. Nature 409: 307-312.
Subauste AR, Burant CF. 2007. Role of FoxO1 in FFA-induced oxidative stress in adipocytes. American Journal of Physiology - Endocrinology and Metabolism 293: E159-E164.
Tissenbaum HA, Guarente L. 2001. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature: 227-230.
Trujillo M, Scherer P. 2005. Adiponectin–journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. Journal of Internal Medicine 257: 167-175.
Unger RH. 2003. The physiology of cellular liporegulation. Annual Review of Physiology 65: 333-347.
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. 1997. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389: 610-614.
Vega GL. 2001. Obesity, the metabolic syndrome, and cardiovascular disease. American Heart Journal 142: 1108-1116.
Walford RL, Harris SB, Gunion MW. 1992. The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans. Proceedings of the National Academy of Sciences 89: 11533-11537.
Walford RL, Mock D, Verdery R, MacCallum T. 2002. Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. Journal of Gerontology: Medical Sciences 57: B211-B214.
Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, Boss O, Hirsch ML, Ribich S, Smith JJ. 2010. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes and Development 24: 1403-1417.
Wang Y, Tissenbaum HA. 2006. Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO. Mechanisms of Ageing and Development 127: 48-56.
Webster BR, Lu Z, Sack MN, Scott I. 2011. The role of sirtuins in modulating redox stressors. Free Radical Biology and Medicine 52: 281-90.
Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. 2004. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430: 686-689.
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA. 2003. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Journal of Clinical Investigation 112: 1821-1830.
Yang T, Sauve AA. 2006. NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity. The AAPS Journal 8: 632-643.
Zhang Q, Wang Z, Chen H, Zhou S, Zheng W, Liu G, Wei Y, Cai H, Liu D, Liang C. 2008. Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovascular Research 80: 191-199.