摘要
MAGED1,也被称作NRAGE或者Dlxin-1.作为一个连结蛋白,它可以和很多蛋白结合,从而行使多种功能。目前已知的有关MAGED1的功能研究大多建立在体外模型上,对于它的生理功能,知识依然很缺乏。
2008年有一例Maged1敲除小鼠被报道,文章显示敲除Maged1会影响发育中的凋亡过程,而在成体中没有明显的可辨异常。我们实验室也构建了一个Maged1敲除小鼠模型。敲除的位置稍有不同,也同样没有从外观上观察到异常。敲除小鼠可以育成并且繁殖。在纯化背景的过程中,我们发现敲除小鼠在晚期发生肥胖。肥胖的时间随小鼠批次的不同而有变化。12月龄已发生肥胖的小鼠表现出体重增加、脂肪增加以及脂肪百分比增加,但是肌肉的质量和同窝的对照相比没有显著差异。正常摄食状态下,血糖和对照持平,禁食后,略有增加,但远没有到达糖尿病的程度。在敲除小鼠体重和对照相差不大的时候,尽管前者体内分泌的胰岛素表现为不足,但是对葡萄糖的耐受能力正常或有所提高;对胰岛素的响应正常或更敏感。利用CLAMS (Comprehensive Lab Animal Monitoring System)对体重相当的小鼠进行监测,发现敲除小鼠的摄食减少,并且活动也减少。细胞水平上,敲除小鼠来源的永生化胚胎成纤维细胞分化成脂肪细胞的能力有所提高,分析表明该细胞对胰岛素更加敏感,可能与增加的IRS-1表达有关。此外胰岛素诱导产生的JNK的活化降低,这也可能导致了细胞对胰岛素的敏感性增加。UV和TNF-a对JNK的活化不受基因敲除的影响,提示JNK对胰岛素的反应降低是特异的。进一步研究发现年轻时的敲除小鼠有体温下降和leptin含量升高的表现。在正常小鼠体内注入leptin,会导致食欲降低、体重减轻。高水平的leptin和缓慢的体重增加提示体内可能存在leptin耐受的情况。在今后的工作中,需要增加敲除小鼠体内的生理指标的测定,用来帮助研究其中的机制。
除了晚期肥胖的表型,在筛选新的生物节律相关蛋白的过程中,我们所建立的Maged1敲除小鼠还被发现有周期缩短的现象。生物钟的存在,使机体可以对外界的变化进行适应和预测。Maged1敲除后,可能对中心的分子调控网络产生影响,从而影响了节律。研究表明,MAGED1可以与RORa结合,通过作用于RORE,增加Bmal1和E4bp4的表达,抑制Rev-erbα的表达。在敲除小鼠内就表现为Bmal1和E4bp4的表达降低,Rev-erbα表达增加。尽管MAGED1本身并不表现出节律,与RORa的结合也没有周期性,但是它增加了体内时钟的稳定性。MAGED1被认为是一个新的节律调控因子,对体内时钟有不可或缺的作用。
MAGED1, also named NRAGE or Dlxin-1, is regarded as an adaptor protein. MAGED1can interact with many proteins and play important roles in several intracellular signaling pathways. However, most conclusions are drawn on the basis of in vitro functional analysis. And the knowledge of the physiological roles of Magedl is limited.
Up till now, only one Magedl knockout mouse has been reported. The deletion just appeared to cause defect in developmental apoptosis. A Magedl knockout mouse strain was also generated in our lab. Similar to those of the reported, the mice are viable, fertile, and normal in gross physical observation. However, the knockout mice were weightier and showed slightly higher levels of blood glucose in fasted status than wild-type mice although these phenotypes were variable among individuals. Compared with the wild-type littermates, the knockout mice exhibited normal or improved glucose tolerance and insulin sensitivity despite of low levels of insulin secretion, when their body weight was comparable. The data from Comprehensive Lab Animal Monitoring System showed that there was almost no difference in oxygen consumption and carbon dioxide production between the knockout and the wild-type mice with undistinguishable body weight. But the knockout mice had less food intake and were less active than wild-type mice. Cellular experiments demonstrated that immortalized Mefs of Magedl knockout mice had a stronger potential to differentiate into adipocytes than those of wild-type mice. In addition, the cells of knockout mice had higher protein levels of IRS-1and continuing phosphorylation of AKT under the stimulation of insulin, indicating that these cells had increased insulin sensitivity. Therefore, the increased adipogenesis observed in knockout Mefs was probably attributed to the improved insulin sensitivity. JNK has been demonstrated to regulate insulin pathway by negative feedback. Interestingly, insulin induced activation of JNK was downregulated in Magedl null cells, which indicated that low activity of JNK was probably responsible for the improved insulin sensitivity. The attenuated activation of JNK by insulin may be unique, because the phosphorylation of JNK caused by UV and TNF-a was comparable in the Maged1knockout and wild-type Mefs. During the further investigation, hypothermia and hyperleptinemia were found in the knockout mice when they were young. In random fed lean mice, administration of exogenous leptin results in anorexia and weight loss. The coexistence of hyperleptinemia and slow weight gain/obesity suggested that there was some kind of leptin resistance in the knockout mice. And more detailed mechanisms are needed to elucidate such late-onset obesity resulting from Maged1knockout.
Besides the late-onset obesity, the most penetrated phenotype of Maged1was shortened circadian period. As we know, the circadian clock plays a central role in physiological adaption and anticipation of day to night alternations. In a genetic screen for novel regulators of circadian rhythms, the Magedl knockout mice were noted for shortened period and altered rest-activity bouts. These circadian phenotypes were proposed to result from a direct change in the core molecular clock network that reduced the robustness of the circadian clock. In vitro and in vivo evidences indicated that MAGED1bound to RORa and then affected the expression of core clock genes, Bmall, Rev-erba and E4bp4, through the Rev-Erba/RORA responsive elements (RORE). Although Magedl was a non rhythmic gene, it enhanced rhythmic input and buffered the irrelevant, perturbing stimuli or noise by binding RORa in a non-circadian way. Magedl was thus identified and defined as a novel circadian regulator, which was indispensable for the robustness of the circadian clock to better serve the organism.
引文
1. Sasaki, A., L. Hinck, and K. Watanabe, RumMAGE-D the members:structure and function of a new adaptor family of MAGE-D proteins. J Recept Signal Transduct Res,2005.25(3):p.181-98.
2. Coll, A.P., et al, SnapShot:the hormonal control of food intake. Cell,2008.135(3):p.572 el-2.
3. Barker, P.A. and A. Salehi, The MAGE proteins:emerging roles in cell cycle progression, apoptosis, and neurogenetic disease. J Neurosci Res,2002.67(6):p.705-12.
4. McPherson, R, Genetic contributors to obesity. Can J Cardiol,2007.23 SupplA:p.23A-27A.
5. Spiegelman, B.M. and J.S. Flier, Obesity and the regulation of energy balance. Cell,2001.104(4): p.531-43.
6. Pold, M., et al. Identification of a new, unorthodox member of the MAGE gene family. Genomics, 1999.59(2):p.161-7.
7. Salehi, A.H., et al, NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis. Neuron,2000.27(2):p.279-88.
8. Masuda, Y., et al., Dlxin-1, a novel protein that binds Dlx5 and regulates its transcriptional function. J Biol Chem,2001.276(7):p.5331-8.
9. vander Bruggen, P., et al., A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science,1991.254(5038):p.1643-7.
10. van der Bruggen, P., et al, A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. J Immunol,2007.178(5):p.2617-21.
11. Finn, O.J., Human tumor immunology at the molecular divide. J Immunol,2007.178(5):p. 2615-6.
12. Chomez, P., et al., An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res,2001.61(14):p.5544-51.
13. Pold, M., et al., Cloning of the first invertebrate MAGE paralogue:an epitope that activates T-cells in humans is highly conserved in evolution. Dev Comp Immunol,2000.24(8):p.719-31.
14. Bischof, J.M., M. Ekker, and R. Wevrick, A MAGE/NDN-like gene in zebrafish. Dev Dyn,2003. 228(3):p.475-9.
15. De Smet, C., et al., DNA methylation is the primary silencing mechanism for a set of germ line-and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol,1999.19(11):p.7327-35.
16. Jungbluth, A.A., et al., CT7 (MAGE-Cl) antigen expression in normal and neoplastic tissues. int J Cancer,2002.99(6):p.839-45.
17. Osterlund, C., et al., Mage-b4, a novel melanoma antigen (MAGE) gene specifically expressed during germ cell differentiation. Cancer Res,2000.60(4):p.1054-61.
18. Jungbluth, A.A., et al., Expression of MAGE-antigens in normal tissues and cancer. Int J Cancer, 2000.85(4):p.460-5.
19. Clotman, F., et al., Cell- and stage-specific expression of mage genes during mouse spermatogenesis. Mamm Genome,2000.11(8):p.696-9.
20. Chomez, P., et al., The SMAGE gene family is expressed in post-meiotic spermatids during mouse germ cell differentiation. Immunogenetics,1996.43(1-2):p.97-100.
21. Takahashi, K., et al., Identification of MAGE-1 and MAGE-4 proteins in spermatogonia and primary spermatocytes of testis. Cancer Res,1995.55(16):p.3478-82.
22. Jay, P., et al., The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nat Genet,1997.17(3):p.357-61.
23. Watr in, F., et al., The mouse Necdin gene is expressed from the paternal allele only and lies in the 7C region of the mouse chromosome 7, a region of conserved synteny to the human Prader-Willi syndrome region. Eur J Hum Genet,1997.5(5):p.324-32.
24. MacDonald, H.R. and R. Wevrick, The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse. Hum Mol Genet,1997.6(11):p.1873-8.
25. Sutcliffe, J.S., et al., Neuronally-expressed necdin gene:an imprinted candidate gene in Prader-Willi syndrome. Lancet,1997.350(9090):p.1520-1.
26. Lee, S., et al. Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the homologous murine imprinting phenotype. Hum Mol Genet,2000.9(12):p.1813-9.
27. Boccaccio,I., et al.. The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region. Hum Mol Genet,1999.8(13):p.2497-505.
28. Muscatelli, F., et al., Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum Mol Genet,2000.9(20):p. 3101-10.
29. Bischof J.M., C.L. Stewart, and R. Wevrick, Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome. Hum Mol Genet,2007.16(22):p.2713-9.
30. Kanber, D., et al., A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome. Eur J Hum Genet,2009.17(5):p.582-90.
31. Bertrand, M., et al., Comparative expression analysis of the MAGED genes during embryogenesis and brain development. Dev Dyn,2004.230(2):p.325-34.
32. Langnaese, K., et al., Expression pattern and further characterization of human MAGED2 and identification of rodent orthologues. Cytogenet Cell Genet,2001.94(3-4):p.233-40.
33. Papageorgio, C., et al.. MA GED2:a novel p53-dissociator. Int J Oncol,2007.31(5):p.1205-11.
34. Fukuda, M.N., et al., Trophinin and tastin, a novel cell adhesion molecule complex with potential involvement in embryo implantation. Genes Dev,1995.9(10):p.1199-210.
35. Nadano, D., et al., Significant differences between mouse and human trophinins are revealed by their expression patterns and targeted disruption of mouse trophinin gene. Biol Reprod,2002. 66(2):p.313-21.
36. Hatakeyama, S., et al., Functional correlation of trophinin expression with the malignancy of testicular germ cell tumor. Cancer Res,2004.64(12):p.4257-62.
37. Baba, T., et al., Trophinin is a potent prognostic marker of ovarian cancer involved in platinum sensitivity. Biochem Biophys Res Commun,2007.360(2):p.363-9.
38. Chen, K. Y., et al., Identification of trophinin as an enhancer for cell invasion and a prognostic factor for early stage lung cancer. Eur J Cancer,2007.43(4):p.782-90.
39. Harada, O., et al., The role of trophinin, an adhesion molecule unique to human trophoblasts, in progression of colorectal cancer. Int J Cancer,2007.121(5):p.1072-8.
40. Fukuda, M.N., K. Sugihara, and J. Nakayama, Trophinin:what embryo implantation teaches us about human cancer. Cancer Biol Ther,2008.7(8):p.1165.
41. Chang, X.Z., et al., Enhanced expression of trophinin promotes invasive and metastatic potential of human gallbladder cancer cells. J Cancer Res Clin Oncol,2009.135(4):p.581-90.
42. Saburi, S., et al., The trophinin gene encodes a novel group of MAGE proteins, magphinins, and regulates cell proliferation during gametogenesis in the mouse. J Biol Chem,2001.276(52):p. 49378-89.
43. Sasaki, M., et al., MAGE-E1, a new member of the melanoma-associated antigen gene family and its expression in human glioma. Cancer Res,2001.61(12):p.4809-14.
44. Di Certo, M.G., et al., NRAGE associates with the anti-apoptotic factor Che-1 and regulates its degradation to induce cell death. J Cell Sci,2007.120(Pt 11):p.1852-8.
45. Salehi, A.H., S. Xanthoudakis, and P.A. Barker, NRAGE, a p75 neurotrophin receptor-interacting protein, induces caspase activation and cell death through a JNK-dependent mitochondrial pathway. J Biol Chem,2002.277(50):p.48043-50.
46. Matsuda,T., et al, The receptor tyrosine kinase Ror2 associates with the melanoma-associated antigen (MAGE) family protein Dlxin-1 and regulates its intracellular distribution. J Biol Chem, 2003.278(31):p.29057-64.
47. Sasaki, A., et al., A RING finger protein Prajal regulates DLx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein, Dlxin-1. J Biol Chem,2002.277(25):p.22541-6.
48. Williams, M.E., et al., UNC5H1 induces apoptosis via its juxtamembrane region through an interaction with NRAGE. J Biol Chem,2003.278(19):p.17483-90.
49. Beattie, M.S., et al., ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury. Neuron,2002.36(3):p.375-86.
50. Kendall, S.E., et al., NRAGE mediates p38 activation and neural progenitor apoptosis via the bone morphogenetic protein signaling cascade. Mol Cell Biol,2005.25(17):p.7711-24.
51. Bragason, B.T. and A. Palsdottir, Interaction of PrP with NRAGE, a protein involved in neuronal apoptosis. Mol Cell Neurosci,2005.29(2):p.232-44.
52. Kuwajima, T., I. Nishimura, and K. Yoshikawa, Necdin promotes GABAergic neuron differentiation in cooperation with Dlx homeodomain proteins. J Neurosci,2006.26(20):p. 5383-92.
53. Kuwajima,T., et al., Necdin interacts with the Msx2 homeodomain protein via MAGE-D1 to promote myogenic differentiation of C2Cl2 cells. J Biol Chem,2004.279(39):p.40484-93.
54. Jordan, B.W., et al., Neurotrophin receptor-interacting mage homologue is an inducible inhibitor of apoptosis protein-interacting protein that augments cell death. J Biol Chem,2001.276(43):p. 39985-9.
55. Matluk, N., et al., A role for NRAGE in NF-kappaB activation through the non-canonical BMP pathway. BMC Biol,2010.8(1):p.7.
56. Wen, C.J., et al., hNRAGE, a human neurotrophin receptor interacting MAGE homologue, regulates p53 transcriptional activity and inhibits cell proliferation. FEBS Lett,2004.564(1-2):p. 171-6.
57. Tian, X.X., et al., BRCA2 suppresses cell proliferation via stabilizing MAGE-D1. Cancer Res, 2005.65(11):p.4747-53.
58. Xue, B., et al., Human NRAGE disrupts E-cadherin/beta-catenin regulated homotypic cell-cell adhesion. Biochem Biophys Res Commun,2005.336(1):p.247-51.
59. Chu, C.S., et al., NRAGE suppresses metastasis of melanoma and pancreatic cancer in vitro and in vivo. Cancer Lett,2007.250(2):p.268-75.
60. Bertrand, M.J., et al., NRAGE, a p75NTR adaptor protein, is required for developmental apoptosis in vivo. Cell Death Differ,2008.15(12):p.1921-9.
61. Rankinen,T., et al., The human obesity gene map:the 2005 update. Obesity (Silver Spring),2006. 14(4):p.529-644.
62. Bray, G.A., S. Paeratakul, and B.M. Popkin, Dietary fat and obesity:a review of animal, clinical and epidemiological studies. Physiol Behav,2004.83(4):p.549-55.
63. Lustig, R.H., Childhood obesity:behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics. Nat Clin Pract Endocrinol Metab,2006.2(8):p.447-58.
64. Shinyama, H., et al., Regulation of melanocortin-4 receptor signaling:agonist-mediated desensitization and internalization. Endocrinology,2003.144(4):p.1301-14.
65. Flier, J.S., AgRP in energy balance:Will the real AgRP please stand up? Cell Metab,2006.3(2): p.83-5.
66. Broberger, C., Brain regulation of food intake and appetite:molecules and networks. J Intern Med, 2005.258(4):p.301-27.
67. Farooqi, I.S., et al., Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med,2003.348(12):p.1085-95.
68. Farooqi, I.S., et al., Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. JClin Invest,2000.106(2):p.271-9.
69. Vaisse, C., et al., Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J Clin Invest,2000.106(2):p.253-62.
70. Flier, J.S., Obesity wars:molecular progress confronts an expanding epidemic. Cell,2004.116(2): p.337-50.
71. Hara, J., et al., Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron,2001.30(2):p.345-54.
72. Chaudhri, O., C. Small, and S. Bloom, Gastrointestinal hormones regulating appetite. Philos Trans R Soc Lond B Biol Sci,2006.361(1471):p.1187-209.
73. Gregoire, F.M., CM. Smas, and H.S. Sul, Understanding adipocyte differentiation. Physiol Rev, 1998.78(3):p.783-809.
74. Rangwala, S.M. and M.A. Lazar, Transcriptional control of adipogenesis. Annu Rev Nutr,2000. 20:p.535-59.
75. Rosen, E.D. and B.M. Spiegelman, Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol, 2000.16:p.145-71.
76. Altshuler, D., et al., The common PPARgamma Pro 12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet,2000.26(1):p.76-80.
77. Deeb, S.S., et al., A Pro 12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet,1998.20(3):p.284-7.
78. Ristow, M., et al., Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med,1998.339(14):p.953-9.
79. Anand, A. and K. Chada, In vivo modulation of Hmgic reduces obesity. Nat Genet,2000.24(4):p. 377-80.
80. Chen, H.C. and R.V. Farese, Jr., DGAT and triglyceride synthesis:a new target for obesity treatment? Trends Cardiovasc Med,2000.10(5):p.188-92.
81. Chen, H.C, Z. Ladha, and R.V. Farese, Jr., Deficiency of acyl coenzyme a.diacylglycerol acyltransferase 1 increases leptin sensitivity in murine obesity models. Endocrinology,2002. 143(8):p.2893-8.
82. Chen, H.C., et al., Increased insulin and leptin sensitivity in mice lacking acyl CoA.diacylglycerol acyltransferase I. J Clin Invest,2002.109(8):p.1049-55.
83. Guilherme, A., et al., Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol,2008.9(5):p.367-77.
84. Kershaw, E.E. and J.S. Flier, Adipose tissue as an endocrine organ. J Clin Endocrinol Metab, 2004.89(6):p.2548-56.
85. Hayakawa, T, et al., Gln27Glu and Argl6Gly polymorphisms of the beta2-adrenergic receptor gene are not associated with obesity in Japanese men. Metabolism,2000.49(9):p.1215-8.
86. Meirhaeghe, A., et al.. Impact of polymorphisms of the human beta2-adrenoceptor gene on obesity in a French population. Int J Obes Relat Metab Disord,2000.24(3):p.382-7.
87. Ukkola, O., et al., Interactions among the alpha2-, beta2-, and beta3-adrenergic receptor genes and obesity-related phenotypes in the Quebec Family Study. Metabolism,2000.49(8):p.1063-70.
88. Osuga, J., et al., Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. Proc Natl Acad Sci U S A,2000.97(2):p.787-92.
89. Haemmerle, G., et al., Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science,2006.312(5774):p.734-7.
90. Martinez-Botas, J., et al, Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nat Genet,2000.26(4):p.474-9.
91. Tansey, J.T., et al., Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc Natl Acad Sci U S A, 2001.98(11):p.6494-9.
92. Lowell, B.B., Adaptive thermogenesis:turning on the heat. Curr Biol,1998.8(15):p. R517-20.
93. Palou, A., et al., The uncoupling protein, thermogenin. Int J Biochem Cell Biol,1998.30(1):p. 7-11.
94. Qiu, J., et al., Transgenic mice overexpressing leptin accumulate adipose mass at an older, but not younger, age. Endocrinology,2001.142(1):p.348-58.
95. Trayhurn, P., Thermoregulation in the diabetic-obese (db/db) mouse. The role of non-shivering thermogenesis in energy balance. Pflugers Arch,1979.380(3):p.227-32.
96. Trayhurn, P. and W.P. James, Thermoregulation and non-shivering thermogenesis in the genetically obese (ob/ob) mouse. Pflugers Arch,1978.373(2):p.189-93.
97. Collins, S., et al., Role of leptin in fat regulation. Nature,1996.380(6576):p.677.
98. Finck, B.N. and D.P. Kelly, PGC-1 coactivators:inducible regulators of energy metabolism in health and disease. J Clin Invest,2006.116(3):p.615-22.
99. McKnight, G.S., et al., Cyclic AMP, PKA, and the physiological regulation of adiposity. Recent Prog Horm Res,1998. S3:p.139-59; discussion 160-1.
100.Cummings, D.E., et al., Genetically lean mice result from targeted disruption of the Rll beta subunit of protein kinase A. Nature,1996.382(6592):p.622-6.
101.Cederberg, A., et al., FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell,2001.106(5):p.563-73.
102.Taniguchi, C.M., B. Emanuelli, and C.R. Kahn, Critical nodes in signalling pathways:insights into insulin action. Nat Rev Mol Cell Biol,2006.7(2):p.85-96.
103. Thirone, A.C., C. Huang, and A. Klip, Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol Metab,2006.17(2):p.72-8.
104.Duncan, R.E., et al., Regulation of lipolysis in adipocytes. Annu Rev Nutr,2007.27:p.79-101.
105.Wahren, J. and K. Ekberg, Splanchnic regulation of glucose production. Annu Rev Nutr,2007.27: p.329-45.
106.Schenk, S., M. Saberi, and J.M. Olefsky, Insulin sensitivity:modulation by nutrients and inflammation. J Clin Invest,2008.118(9):p.2992-3002.
107.Unger, R.H., The hyperleptinemia of obesity-regulator of caloric surpluses. Cell,2004.117(2):p. 145-6.
108. Lee, Y., et al., Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. J Biol Chem,2001.276(8):p.5629-35.
109.Minokoshi, Y., et al, AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature,2004.428(6982):p.569-74.
110.Andersson, U., et al., AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem,2004.279(13):p.12005-8.
111.Hastings, M.H., Central clocking. Trends Neurosci,1997.20(10):p.459-64.
112. Welsh, D.K., et al, Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron,1995.14(4):p.697-706.
113.Allada, R., et al, Stopping time:the genetics of fly and mouse circadian clocks. Annu Rev Neurosci,2001.24:p.1091-119.
114.Lowrey, P.L. and J.S. Takahashi, Mammalian circadian biology:elucidating genome-wide levels of temporal organization. Annu Rev Genomics Hum Genet,2004.5:p.407-41.
115.Reppert, S.M. and D.R. Weaver, Coordination of circadian timing in mammals. Nature,2002. 418(6901):p.935-41.
116.Schibler, U., The daily rhythms of genes, cells and organs. Biological clocks and circadian timing in cells. EMBO Rep,2005.6 Spec No:p. S9-13.
117. Young, M. W. and S.A. Kay, Time zones:a comparative genetics of circadian clocks. Nat Rev Genet, 2001.2(9):p.702-15.
118.Preitner, N., et al., The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell,2002.110(2):p.251-60.
119.Sato, T.K., et al., A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron,2004.43(4):p.527-37.
120.Ueda, H.R., et al., System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet,2005.37(2):p.187-92.
1. Bertrand, M., et al., Comparative expression analysis of the MAGED genes during embryogenesis and brain development. Dev Dyn,2004.230(2):p.325-34.
2. Pold, M., et al., Identification of a new, unorthodox member of the MAGE gene family. Genomics, 1999.59(2):p.161-7.
1. Kitamura, T., et al., Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor. Mol Cell Biol,2001.21(16):p.5624-30.
2. Nilausen, K. and H. Green, Reversible arrest of growth in G1 of an established fibroblast line (3T3). Exp Cell Res,1965.40(1):p.166-8.
3. Estill, S.J. and J.A. Garcia, A marker assisted selection protocol (MASP) to generate C57BL/6J or 129S6/SvEvTac speed congenic or consomic strains. Genesis,2000.28(3-4):p.164-6.
4. Bertrand, M.J., et al., NRAGE, a p75NTR adaptor protein, is required for developmental apoptosis in vivo. Cell Death Differ,2008.15(12):p.1921-9.
5. Sal eh i, A.H., S. Xanthoudakis, and P. A. Barker, NRAGE, a p75 neurotrophin receptor-interacting protein, induces caspase activation and cell death through a JNK-dependent mitochondrial pathway. J Biol Chem,2002.277(50):p.48043-50.
6. Lee, Y.H., et al., c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem,2003.278(5):p.2896-902.
7. Lamia, K.A., et al., Increased insulin sensitivity and reduced adiposity in phosphatidylinositol 5-phosphate 4-kinase beta-/-mice. Mol Cell Biol,2004.24(11):p.5080-7.
8. Elchebly. M., et al., Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science,1999.283(5407):p.1544-8.
9. Yu, S., et al., Increased insulin sensitivity in Gsalpha knockout mice. J Biol Chem,2001.276(23):p. 19994-8.
10. Ferrara, C.M. and S.W. Cushman, GLUT4 trafficking in insulin-stimulated rat adipose cells: evidence that heterotrimeric GTP-binding proteins regulate the fusion of docked GLUT4-containing vesicles. Biochem J,1999.343 Pt 3 p.571-7.
11. Green, A., R.M. Carroll, and S.B. Dobias, Desensitization of beta-adrenergic receptors in adipocytes causes increased insulin sensitivity of glucose transport. Am J Physiol,1996.271(2 Pt 1):p. E271-6.
12. Klein, H.H., et al., The relationship between insulin binding, insulin activation of insulin-receptor tyrosine kinase, and insulin stimulation of glucose uptake in isolated rat adipocytes. Effects of isoprenaline. Biochem J,1991.274 (Pt 3):p.787-92.
13. Shanahan, M.F., B.M. Edwards, and A.E. Ruoho, Interactions of insulin, catecholamines and adenosine in the regulation of glucose transport in isolated rat cardiac myocytes. Biochim Biophys Acta,1986.887(1):p.121-9.
14. Taylor, W.M., M.L. Mak, and M.L. Hal per in, Effect of 3':5'-cyclic AMP on glucose transport in rat adipocytes. Proc Natl Acad Sci U S A,1976.73(12):p.4359-63.
15. Hara, J., et al., Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron,2001.30(2):p.345-54.
16. Hanada, R., et al, Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway. Nat Med,2004.10(10):p.1067-73.
17. Rahmouni, K., et al., Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome. J Clin Invest,2008.118(4):p.1458-67.
18. Qiu, J., et al., Transgenic mice overexpressing leptin accumulate adipose mass at an older, but not younger, age. Endocrinology,2001.142(1):p.348-58.
19. Oliver, P., C. Pico, and A. Palou, Ontogenesis of leptin expression in different adipose tissue depots in the rat. Pflugers Arch,2001.442(3):p.383-90.
20. Tamemoto, H., et al., Insulin resistance syndrome in mice deficient in insulin receptor substrate-1. Ann N Y Acad Sci,1997.827:p.85-93.
21. Fruhbeck, G., Overview of adipose tissue and its role in obesity and metabolic disorders. Methods Mol Biol,2008.456:p.1-22.
22. Foster, M. T. and T.J. Bartness, Sympathetic but not sensory denervation stimulates white adipocyte proliferation. Am J Physiol Regul Integr Comp Physiol,2006.291(6):p. R1630-7.
1. Albrecht, U. and G. Eichele, The mammalian circadian clock. Curr Opin Genet Dev.2003.13(3): p.271-7.
2. Hastings, M.H., Circadian clocks:self-assembling oscillators? Curr Biol,2003.13(17):p. R681-
3. Allada, R., et al., Stopping time:the genetics of fly and mouse circadian clocks. Annu Rev Neurosc 2001.24:p.1091-119.
4. Lowrey, PL. and J.S. Takahashi, Mammalian circadian biology:elucidating genome-wide levels of temporal organization. Anmi Rev Genomics Hum Genet,2004.5:p.407-41.
5. Reppert, S. M. and D. R. Weaver, Coordination of circadian timing in mammals. Nature,2002. 418(6901):p.935-41.
6. Schibler, U., The daily rhythms of genes, cells and organs. Biological clocks and circadian timing in cells. EMBO Rep,2005.6 Spec No:p. S9-13.
7. Young, M. W. and S.A. Kay, Time zones:a comparative genetics of circadian clocks. Nat Rev Genet, 2001.2(9):p.702-15.
8. Preitner, N., et al, The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell,2002.110(2):p.251-60.
9. Sato, T.K., et al, A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron,2004.43(4):p.527-37.
10. Ueda, H.R., et al., System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet,2005.37(2):p.187-92.
11. Xu, Y., et al., Functional consequences of a CKldelta mutation causing familial advanced sleep phase syndrome. Nature,2005.434(7033):p.640-4.
12:Xu, Y., et al., Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell,2007.128(1):p.59-70.
13. Shearman, L.P., et al., Interacting molecular loops in the mammalian circadian clock. Science, 2000.288(5468):p.1013-9.
14. Yoo, S.H., et al, PER1OD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci U S A,2004. 101(15):p.5339-46.
15. Yamazaki, S., et al, Resetting central and peripheral circadian oscillators in transgenic rats. Science,2000.288(5466):p.682-5.
16. Abbondanzo, S.J., I. Gadi, and C.L. Stewart, Derivation of embryonic stem cell lines. Methods Enzymol,1993.225:p.803-23.
17. Izumo, M., C.H. Johnson, and S. Yamazaki, Circadian gene expression in mammalian fibroblasts revealed by real-time luminescence reporting:temperature compensation and damping. Proc Natl Acad Sci U S A,2003.100(26):p.16089-94.
18. Nowak, D.E., B. Tian, and A,R. Brasier, Two-step cross-linking method for identification of NF-kappaB gene network by chromatin immunoprecipitation. Biotechniques,2005.39(5):p. 715-25.
19. Zeng, P.Y., et al., In vivo dual cross-linking for identification of indirect DNA-associated proteins by chromatin immunoprecipitation. Biotechniques,2006.41(6):p.694,696,698.
20. Guguen-Guillouzo, C., M. Bourel, and A. Guillouzo, Human hepatocyte cultures. Prog Liver Dis, 1986.8:p.33-50.
21. Vitaterna, M.H., et al, The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude. Proc Natl Acad Sci U S A,2006.103(24):p.9327-32.
22. Brown, S.A., et al., Molecular insights into human daily behavior. Proc Natl Acad Sci U S A,2008. 105(5):p.1602-7.
23. Adelmant, G., et al., A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity. Proc Natl Acad Sci U S A,1996.93(8):p.3553-8,
24. Delerive, P., W.W. Chin, and C.S. Suen, Identification of Reverb(alpha) as a novel ROR(alpha) target gene. J Biol Chem,2002.277(38):p.35013-8.
25. Bertrand, M., et al., Comparative expression analysis of the MAGED genes during embryogenesis and brain development. Dev Dyn,2004.230(2):p.325-34.
26. Wright, K.P., Jr., et al., Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans. Proc Natl Acad Sci U S A,2001.98(24):p. 14027-32.
27. Dodd, A.N., et al., Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage. Science,2005.309(5734):p.630-3.
28. Mackey, S.R. and S.S. Golden, Winding up the cyanobacterial circadian clock. Trends Microbiol, 2007.15(9):p.381-8.
29. Wijnen, H. and M. W. Young, Interplay of circadian clocks and metabolic rhythms. Annu Rev Genet, 2006.40:p.409-48.
30. Chawla, A., et al., Nuclear receptors and lipid physiology:opening the X-files. Science,2001. 294(5548):p.1866-70.