研究生: |
孫筠雅 Sun, Yun-Ya |
---|---|
論文名稱: |
幼年小鼠給予C16神經醯胺對於其成鼠後行為與記憶之影響 Effect of C16-ceramide at early lives exposure on behavior/memory of adult mice |
指導教授: |
林炎壽
Lin, Yenshou |
學位類別: |
碩士 Master |
系所名稱: |
生命科學系 Department of Life Science |
論文出版年: | 2017 |
畢業學年度: | 106 |
語文別: | 中文 |
論文頁數: | 58 |
中文關鍵詞: | 神經醯胺 、胰島素拮抗 、認知受損 、高脂飲食 |
英文關鍵詞: | ceramide, insulin resistance, cognitive impairment, high fat diet |
DOI URL: | https://doi.org/10.6345/NTNU202201912 |
論文種類: | 學術論文 |
相關次數: | 點閱:130 下載:2 |
分享至: |
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報 |
神經醯胺為一種重要的細胞結構,參與許多細胞活動,在自然界中多以長碳鏈之形式存在。有研究指出小鼠攝取高油脂飲食會造成體內神經醯胺濃度增加,並使得體內葡萄糖濃度受到影響,而產生胰島素拮抗現象。研究也發現,許多代謝相關疾病,如:第二型糖尿病、肥胖等,均會增加病人認知受損的風險,相反的,若是施予認知受損病人胰島素增敏劑,可改善認知受損情況,不過在認知損傷與胰島素拮抗之間之關係還需要更深入之探討。目前並沒有研究針對神經醯胺對於幼鼠成長過程之生理及行為影響作探討。所以本實驗以三週大的小鼠於皮下注射C16神經醯胺,模擬可能因飲食所導致的堆積,也以高脂飲食誘導小鼠發生肥胖,檢測神經醯胺的影響。結果顯示,C16神經醯胺對於小鼠體重及血糖,或在餵食高油脂飲食後的體重及血糖等,皆沒有顯著的影響。在動物行為的結果發現,肥胖會大幅降低小鼠的自發探索能力。注射C16神經醯胺之小鼠,在莫氏水迷津實驗中,不論是攝食何種飼料的小鼠,其短期、長期記憶測驗皆有顯著地提升。進一步研究發現經過C16神經醯胺及油酸處理過的小鼠初級神經細胞,與記憶相關之蛋白CaMK II T286之磷酸化量會上升。綜合以上,幼年給予C16神經醯胺之小鼠,於成鼠時其記憶行為似乎有增進的現象,其機制有待進一步探討,但由體外實驗顯示可能與增進CaMK II磷酸化有關。
Ceramide is an important membrane structure involving many different functions in the cell. It naturally occurrs 16 to 24 carbons in length. There are reports indicate that mice fed with high fat diet can cause ceramide accumulation, leading to insulin resistance. In addition, many metabolic diseases such as type 2 diabetes and obesity might increase the risk of developing mild cognitive impairment. In contrast, treatment with insulin-sensitizing agents could improve the cognitive performance. Thus far, there is no evidence demonstrating the relationship between cognitive impairment and insulin resistance. Likewise, there is no report regarding the effect of ceramide given at childhood on adult memory behavior. Three-weeks old mice were injected with C16 ceramide or mineral oil for a month. These mice were further fed with normal chow or high fat diet. The results show that there are no significant differences on mice’s body weight and blood glucose between C16 ceramide treatment and control. Obesity caused by high fat diet significant affects the locomotor activity of mice. Interestingly, C16 ceramide could promote the short-term and long-term memory in ether diet these mice were given. Furthermore, p-CaMK II T286 was increased in the primary neurons treated with C16 ceramide in vitro. Taken together, C16 ceramide given at childhood could enhance the memory behavior at adult mice. It is possible to link to the change of CaMK II activity. The detail molecular mechanism remains to be investigated.
Alberini, C. M. (2009). Transcription factors in long-term memory and synaptic plasticity. Physiol Rev, 89, 11521199.
Anderson, M. (2005). Calmodulin kinase signaling in heart: an intriguing candidate target for therapy of myocardial dysfunction and arrhythmias. Pharmacol Therapeut, 106, 39–55.
Antunes, M. & Biala, G. (2012). The novel object recognition memory: neurobiology, test procedure, and its modification. Cogn Process, 13, 93110.
Arana, L., Gangoiti, P., Ouro, A., Trueba, M., & Gómez-Muñoz, A. (2010). Ceramide and ceramide 1-phosphate in health and disease. Lipids Health Dis, 9, 115.
Bauer, I., Hughes, M., Rowsell, R., Cockerell, R., Pipingas, A., Crewther, S., & Crewther, D. (2014). Omega-3 supplementation improves cognition and modifies brain activation in young adults. Hum Psychopharmacol, 29, 133144.
Blázquez, E., Velázquez, E., Hurtado-Carneiro, V., & Ruiz-Albusac, J. M. (2014). Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease. Front Endocrinol, 5, 161165.
Blouin, C. M., Prado C., Takane K. K., Lasnier, F., Garcia-Ocana, A., Ferre, P., Dugail, I., & Hajduch, E. (2010). Plasma membrane subdomain compartmentalization contributes to distinct mechanisms of ceramide action on insulin signaling. Diabetes, 59, 600610.
Bourbon, N. A., Yun, J., & Kester, M. (2000). Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex. J Biol Chem, 275, 3561735623.
Bruce, C. R., Risis, S., Babb, J. R., Yang, C., Lee-Young, R. S., Henstridge, D. C., & Febbraio, M. A. (2013). The sphingosine-1-phosphate analog FTY720 reduces muscle ceramide content and improves glucose tolerance in high fat-fed male mice. Endocrinology, 154, 6576.
Chavez, J. A., Holland, W. L., Bär, J., Sandhoff, K., & Summers, S. A. (2005). Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling. J Biol Chem, 280, 2014820153.
Cowart, L. A. (2008). Sphingolipids: players in the pathology of metabolic disease. Trends Endocrinol Metab, 20, 3442.
Frangioudakis, G., Diakanastasis, B., & Liao, B. M. (2013). Ceramide accumulation in L6 skeletal muscle cells due to increase activity of ceramide synthase isoform has opposing effects on insulin action to those caused by palmitate treatment. Diabetologia, 56, 26972701.
Fraulob, J. C., Ogg-Diamantino, R., Fernandes-Santos, C., Aguila, M. B., & Mandarim-de-Lacerda, C. A. (2010). A mouse model of metabolic syndrome: insulin resistance, fatty liver and non-alcoholic fatty pancreas disease (NAFPD) in C57BL/6 mice fed a high fat diet. J Clin Biochem Nutr, 46, 212223.
Gangoiti, P., Camacho, L., Arana, L., Ouro, A., Granado, M. H., Brizuela, L., Casas, J., Fabrias, G., Abad, J. L., Delgado, A., & Gomez-Munoz, A. (2010). Control of metabolism and signaling of simple bioactive sphingolipids: Implications in disease. Prog Lipid Res, 49, 316334.
Groener, J. E., Poorthuis, B. J., Kuiper, S., Helmond, M. T., Hollak, C. E., & Aerts, J. M. (2007). HPLC for simultaneous quantification of total ceramide, glucosylceramide, and ceramide trihexoside concentrations in plasma. Clin Chem, 23, 742747.
Hage-Hassan, R., Bourron, O., & Hajduch, E. (2014). Defect of insulin signal in peripheral tissues: Important role of ceramide. World J Diabetes, 5, 244–257.
Haimovitz-Friedman, A., Kan, C. C., Ehleiter, D., Persau, R. S., McLoughlin, & M., Fuks, Z. (1994). Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med, 180, 525535.
Hajduch, E., Balendran, A., Batty, I. H., Litherland, G. J., Blair, A. S., Downes, C. P., & Hundal, H. S. (2001). Ceramide impairs the insulindependent membrane recruitment of protein kinase B leading to a loss in downstream signalling in L6 skeletal muscle cells. Diabetologia, 44, 173-183.
Hannun, Y. A., & Obeid, L. M. (2008). Principles of bioactive lipid signaling: lessons from sphingolipids. Nat Rev Mol Cell Biol, 9, 139150.
Hassan, R. H., Bourron, O., & Hajduch, E. Defect of insulin signal in peripheral tissues: important role of ceramide. (2014). World J Diabetes, 5, 244257.
Hla, T., & Kolesnick, R. (2014). C16:0-Ceramide signals insulin resistance. Cell Metab, 20, 703705.
Holland, W. L., Brozinick, J. T., Wang, L. P., Hawkins, E. D., Sargent, K. M., Liu, Y., Narra, K., Hoehn, K. L., Knotts, T. A., & Siesky, A. (2007). Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab, 5, 167–179.
Holland, W. L., & Summers, S. A. (2008). Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev, 29, 381402.
Holland, W. L., Adams, A. C., Brozinick, J. T., Bui, H. H., Miyauchi, Y., Kusminski, C. M., Bauer, S. M., Wade, M., Singhal, E., Cheng, C. C., Volk, K., Kuo, M. S., Gordillo, R., Kharitonenkov, A., & Scherer, P. E. (2013). An FGF21-Adiponectin-Ceramide axis controls energy expenditure and insulin action in mice. Cell Metab, 17, 970977.
Hsieh, C. T., Chuang, J. H., Yang W. C., Yin, Y. & Lin, Y. (2014). Ceramide inhibits insulin-stimulated Akt phosphorylation through activation of Rheb/mTORC1/S6K signaling in skeletal muscle. Cell Signal, 26, 14001408.
Ichi, I., Nakahara, K., Kiso, K., & Kojo, S. (2007). Effect of dietary cholesterol and high fat on ceramide concentration in rat tissues. Nutrition, 23, 570574.
Ikonen, E., & Vainio, S. (2005). Lipid microdomains and insulin resistance: Is there a connection? Sic Stke, 268, pe3.
JeBailey, L., Wanono, O., Niu, W., Roessler, J., Rudich, A., & Klip, A. (2007). Ceramide- and oxidant-induced insulin resistance involve in muscle cells. Diabetes, 56, 394403.
Karahatay, S., Thomas, K., Koybasi, S., Senkal, C. E., Elojeimy, S., & Liu, X. (2007). Clinical relevance of ceramide metabolism in the pathogenesis of human head and neck squamous cell carcinoma (HNSCC): Attenuation of C(18)-ceramide in HNSCC tumors correlates with lymphovascular invasion and nodal metastasis. Cancer Lett, 256, 101–111.
Kealy, L., Bennett, R., Woods, B., & Lowry, J. P. (2017). Real-time changes in hippocampal energy demands during a spatial working memory task. Behav Brain Res, 326, 5968.
Lahiri, S., Park, H., Laviad, E. L., Lu, X., Bittman, R., & Futerman, A. H. (2009). Ceramide synthesis is modulated by the sphingosine analog FTY720 via a mixture of uncompetitive and noncompetitive inhibition in an Acyl-CoA chain length-dependent manner. J Biol Chem, 284, 1609016098.
Langeveld, M., & Aerts, J. M. (2009). Glycosphingolipids and insulin resistance. Prog Lipid Res, 48, 196205.
Lisman, J. (1994). The CaM kinase II hypothesis for the storage of synaptic memory. Trends Neurosci, 17, 406–412.
Lisman, J., Yasuda, R., & Raghavachari, S. (2012). Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci, 13, 169182.
Ma, L., Wang, J., & Yun, L. (2015). Insulin resistance and cognitive dysfunction. Clinica Chimica Acta, 444, 18–23.
Maceyka, M., Harikumar, K. B., Milstien, S., & Spiegel, S. (2012). Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol, 22, 5060.
Mayford, M., Wang, J., Kandel, E. R., & O'Dell, T. J. (1995). CaMKII regulates the frequency-response function of hippocampal synapses for the production of both LTD and LTP. Cell, 81, 891–904.
Merrill, A. H. (2002). De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J Biol Chem, 277, 25843-25846.
Morales, A., Lee, H., Goni, F. M., Kolesnick, R., & Fernandez-Checa, J. C. (2007). Sphingolipids and cell death. Apoptosis, 12, 923939.
Morigny, P., Houssier, M., Mouisel, E., & Langin, D. (2016). Adipocyte lipolysis and insulin resistance. Biochimie, 125, 259266.
Morris, J. K., Vidoni, E. D., & Honea, R. A. (2014). Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiol Aging, 35, 585–589.
Morris, R. (1984). Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods, 11, 4760.
Obanda, D. N., Yu, Y., Wang Z. Q., & Cefalu, W. T. (2015). Modulation of sphingolipid metabolism with calorie restriction enhances insulin action in skeletal muscle. J Nutr Biochem, 26, 687–695.
Pearce, J. (1983). Fatty acid synthesis in liver and adipose tissue. P Nutr Soc, 2, 263–271.
Peng, S., Zhang, Y., Zhang, J., Wang, H., & Ren, B. (2010). ERK in learning and memory: a review of recent research. Int J Mol Sci, 11, 222232.
Reger, M. A., Watson, G. S., Green, P. S., Wilkinson, C. W., Baker, L. D., Cholerton, B., Fishel, M. A., Plymate, S. R., Breitner, J. C., DeGroodt, W., Mehta, P., & Craft, S. (2008). Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology, 70, 440448.
Poulsen, D. J., Standing, D., Bullshields, K., Spencer, K., Micevych, P. E., & Babcock, A. M. (2007). Overexpression of hippocampal Ca2+/calmodulin-dependent protein kinase II improves spatial memory. J Neurosci Res, 85, 735–739.
Samad, F., Hester, K. D., Yang, G., Hannun, Y. A., & Bielawski, J. (2006). Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes, 55, 25792587.
Senkal, C. E., Ponnusamy, S., Manevich, Y., Meyers-Needham, M., Saddoughi, S. A., & Mukhopadyay, A. (2011). Alteration of ceramide synthase 6/C16-ceramide in-duces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2þand ER/Golgi membrane network. J Biol Chem, 286, 42446–42458.
Shen, K., Teruel, M. N., Connor, J. H., Shenolikar, S. & Meyer, T. (2000). Molecular memory by reversible translocation of calcium/calmodulin-dependent protein kinase II. Nat Neurosci, 3, 881886.
Siskind, L. J., Kolesnick, R. N., & Colombini, M. (2006). Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion, 6, 118–125.
Sordillo, L. A., Sordillo, P. P., & Helson, L. (2016). Sphingosine kinase inhibitors as maintenance therapy of glioblastoma after ceramide-induced response. Anticancer Res, 36, 20852096.
Stiban, J., Fistere, D., & Colombini, M. (2006). Dihydroceramide hinders ceramide channel formation: Implications on apoptosis. Apoptosis, 11, 773–780.
Stonehouse, W., Conlon, C. A., Podd, J., Hill, S. R., Minihane, A. M., Haskell, C., & Kennedy, D. (2013). DHA supplementation improved both memory and reaction time in healthy young adults: a randomized controlled trial. Am J Clin Nutr, 97, 11341143.
Strack, S., Choi, S., Lovinger, D. M., & Colbran, R. J. (1997). Translocation of autophosphorylated calcium/calmodulin-dependent protein kinase II to the postsynaptic density. J Biol Chem, 272, 13467–13470.
Sugita, M., Iwamori, M., Evans, J., McCluer, R. H., Dulaney, J. T., & Moser, H. W. (1974). High performance liquid chromatography of ceramides: application to analysis in human tissues and demonstration of ceramide excess in Farber's disease. J Lipid Res, 15, 223226.
Summers, S. A. (2006). Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res, 45, 4272.
Sun, Q. J. (2003). Research and development of natural ceramide. China Oils and Fats, 2, 6061.
Tabatadze, N., Savonenko, A., Song, H., Bandaru, V. V. R., Chu, M., & Haughey, N. J. (2010). Inhibition of neutral sphingomyelinase-2 perturbs brain sphingolipid balance and spatial memory in mice. J Neurosci Res, 88, 29402951.
Tucsek, Z., Toth, P., & Sosnowska, D. (2014). Obesity in aging exacerbates blood-brain barrier disruption, neuro inflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol A Biol Sci Med Sci, 69, 1212–1226.
Turpin, S. M., Nicholls, H. T., Willmes, D. M., Mourier, A., Brodesser, S., Wunderlich, C. M., Mauer, J., Xu, E., Hammerschmidt, P., Bro ̈nneke, H. S. Trifunovic, A. LoSasso, G., Wunderlich, F. T., Kornfeld, J. W. Blu ̈ her, M., Kro ̈nke, M., & Bru ̈ ning, J. C. (2014). Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab, 20, 678686.
Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., & Thomas, G. (2004). Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature, 431, 200215.
Verdelho, A., Madureira, S., Ferro, J. M., Basile, A. M., Chabriat, H., Erkinjuntti, T., Fazekas, F., Hennerici, M., O'Brien, J., Pantoni, L., Salvadori, E., Scheltens, P., Visser, M. C., Wahlund, L. O., Waldemar, G., Wallin, A., & Inzitari, D. (2007). Differential impact of cerebral white matter changes, diabetes, hypertension and stroke on cognitive performance among non-disabled elderly. J Neurol Neurosurg Psychiatry, 78, 13251330.
Yamauchi, T. (2005). Neuronal Ca2+/calmodulin-dependent protein kinase II-discovery, progress in a quarter of a century, and perspective: implication for learning and memory. Biol Pharm Bull, 28, 1342–1354.
Yurko-Mauro, K., Alexander, D. D., & Van Elswyk, M. E. (2015). Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One, 18, 118.