The Role of Adipose-Derived Inflammatory Cytokines in Type 1 Diabetes—Adipose Tissue and T1D

作者: 邵 兰 , 冯博雅 , 张钰莹 , 周焕娇 , 纪卫东 , 王 敏 :中山大学附属第一医院转化医学中心,广东 广州;

关键词: 脂肪细胞细胞因子I型糖尿病SENP1SUMO化NF-κB必要分子Adipocyte Cytokine Type 1 Diabetes SENP1 SUMOylation NF-κB Essential Molecule

脂肪细胞的功能紊乱与糖尿病的发生有关。近来有研究表明,脂肪组织不仅仅是储存脂肪和调节脂类代谢的组织,同时也是最大的免疫功器官,脂肪细胞可通过分泌细胞因子来影响免疫功能。特异性敲除了脂肪细胞的SUMO特异蛋白酶SENP1基因的小鼠会出现I型糖尿病(type-1 diabetes mellitus, T1DM)的症状。胰腺周围脂肪组织(peri-pancreatic adipocytes, PATs)在胰腺功能中发挥了全身效应以及旁分泌作用与糖尿病的发生密切相关。胰腺周围的脂肪组织与其他脂肪储存组织相比,产生了更多的促炎细胞因子。这些促炎细胞因子对胰岛有直接的细胞毒性作用,导致邻近胰岛的炎症反应,破坏胰腺中的免疫平衡。NF-κB必要分子(NF-κB essential molecule, NEMO) SUMO化,可以增强NF-κB活性、细胞因子产生以及胰腺的炎症反应。NF-κB抑制剂为阻断炎症反应、缓解1型糖尿病提供了新的治疗策略。因此胰腺周围脂肪组织的脂肪细胞在糖尿病发生时的胰腺免疫调节建立中可能起着重要作用,为I型糖尿病的发生发展提供了可能的新的分子发病机制。

Abstract: Adipocyte dysfunction correlates with the development of diabetes. Recent studies suggest that adipose tissue is not simply the organ that stores fat and regulates lipid metabolism, but also is the largest endocrine organ with immune functions. Mice with an adipocyte-specific deletion of a SUMO- specific protease SENP1 develop symptoms of type-1 diabetes mellitus (T1DM) resulted from beta cell damage. Cytokine profiling indicates that peri-pancreatic adipocytes (PATs) of SENP1-dificient mice have increased proinflammatory cytokine production compared with other adipose depots. Proinflammatory cytokines originated from PATs have direct cytotoxic effects on pancreatic islets, and also increase infiltration of immune cells by augmenting CCL5 expression in adjacent pancreatic islets. Molecular analyses support that SUMOylation of NF-κB essential molecule (NEMO) in PATs leads to increased NF-κB activity, cytokine production and pancreatic inflammation. Therapeutic attempting to ameliorate the T1DM phenotype should consider using of NF-κB inhibitor against adipocyte inflammation.

文章引用: 邵 兰 , 冯博雅 , 张钰莹 , 周焕娇 , 纪卫东 , 王 敏 (2016) 脂肪炎症细胞因子在I型糖尿病中的作用—脂肪组织与I型糖尿病。 千人·生物, 3, 1-6. doi: 10.12677/QRB.2016.31001


[1] Lehuen, A., Diana, J., Zaccone, P. and Cooke, A. (2010) Immune Cell Crosstalk in Type 1 Diabetes, Nature Reviews. Immunology, 10, 501-513.

[2] American Diabetes Association (2011) Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 34, S62-S69.

[3] Navarro-Gonzalez, J.F. and Mora-Fernandez, C. (2008) The Role of Inflammatory Cytokines in Diabetic Nephropathy. Journal of the American Society of Nephrology, 19, 433-442.

[4] Tilg, H. and Moschen, A.R. (2006) Adipocytokines: Mediators Linking Adipose Tissue, Inflammation and Immunity, Nature Reviews. Immunology, 6, 772-783.

[5] Greenberg, A.S. and Obin, M.S. (2006) Obesity and the Role of Adipose Tissue in Inflammation and Metabolism. The American Journal of Clinical Nutrition, 83, 461S-465S.

[6] Odegaard, J.I. and Chawla, A. (2012) Connecting Type 1 and Type 2 Diabetes through Innate Immunity. Cold Spring Harbor Perspectives in Medicine, 2, Article ID: a007724.

[7] Rocha, V.Z. and Folco, E.J. (2011) Inflammatory Concepts of Obesity. International Journal of Inflammation, 2011, Article ID: 529061.

[8] Chandran, M., Phillips, S.A., Ciaraldi, T. and Henry, R.R. (2003) Adiponectin: More Than Just Another Fat Cell Hormone? Diabetes Care, 26, 2442-2450.

[9] Gesta, S., Bluher, M., Yamamoto, Y., Norris, A.W., Berndt, J., Kralisch, S., Boucher, J., Lewis, C. and Kahn, C.R. (2006) Evidence for a Role of Developmental Genes in the Origin of Obesity and Body Fat Distribution. Proceedings of the National Academy of Sciences of the United States of America, 103, 6676-6681.

[10] Tchkonia, T., Lenburg, M., Thomou, T., Giorgadze, N., Frampton, G., Pirtskhalava, T., Cartwright, A., Cartwright, M., Flanagan, J., Karagiannides, I., Gerry, N., Forse, R.A., Tchoukalova, Y., Jensen, M.D., Pothoulakis, C. and Kirkland, J.L. (2007) Identification of Depot-Specific Human Fat Cell Progenitors through Distinct Expression Profiles and Developmental Gene Patterns. American Journal of Physiology. Endocrinology and Metabolism, 292, E298-E307.

[11] Franco-Pons, N., Gea-Sorli, S. and Closa, D. (2010) Release of Inflammatory Mediators by Adipose Tissue during Acute Pancreatitis. The Journal of Pathology, 221, 175-182.

[12] Heni, M., Machann, J., Staiger, H., Schwenzer, N.F., Peter, A., Schick, F., Claussen, C.D., Stefan, N., Haring, H.U. and Fritsche, A. (2010) Pancreatic Fat Is Negatively Associated with Insulin Secretion in Individuals with Impaired Fasting Glucose and/or Impaired Glucose Tolerance: A Nuclear Magnetic Resonance Study. Diabetes/Metabolism Research and Reviews, 26, 200-205.

[13] Rippe, C., Berger, K., Mei, J., Lowe, M.E. and Erlanson-Albertsson, C. (2003) Effect of Long-Term High-Fat Feeding on the Expression of Pancreatic Lipases and Adipose Tissue Uncoupling Proteins in Mice. Pancreas, 26, e36-e42.

[14] Shao, L., Zhou, H.J., Zhang, H., Qin, L., Hwa, J., Yun, Z., Ji, W. and Min, W. (2015) SENP1-Mediated NEMO DeSUMOylation in Adipocytes Limits Inflammatory Responses and Type-1 Diabetes Progression. Nature Communications, 6, 8917.

[15] Chatterjee, T.K., Stoll, L.L., Denning, G.M., Harrelson, A., Blomkalns, A.L., Idelman, G., Rothenberg, F.G., Neltner, B., Romig-Martin, S.A., Dickson, E.W., Rudich, S. and Weintraub, N.L. (2009) Proinflammatory Phenotype of Perivascular Adipocytes: Influence of High-Fat Feeding. Circulation Research, 104, 541-549.

[16] Pihoker, C., Gilliam, L.K., Hampe, C.S. and Lernmark, A. (2005) Autoantibodies in Diabetes. Diabetes, 54, S52-S61.

[17] van Belle, T.L., Coppieters, K.T. and von Herrath, M.G. (2011) Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies. Physiological Reviews, 91, 79-118.

[18] Hu, F.B., Meigs, J.B., Li, T.Y., Rifai, N. and Manson, J.E. (2004) Inflammatory Markers and Risk of Developing Type 2 Diabetes in Women. Diabetes, 53, 693-700.

[19] Hoglund, P., Mintern, J., Waltzinger, C., Heath, W., Benoist, C. and Mathis, D. (1999) Initiation of Autoimmune Diabetes by Developmentally Regulated Presentation of Islet Cell Antigens in the Pancreatic Lymph Nodes. The Journal of Experimental Medicine, 189, 331-339.

[20] Akirav, E., Kushner, J.A. and Herold, K.C. (2008) Beta-Cell Mass and Type 1 Diabetes: Going, Going, Gone? Diabetes, 57, 2883-2888.

[21] Carvalho-Pinto, C., Garcia, M.I., Gomez, L., Ballesteros, A., Zaballos, A., Flores, J.M., Mellado, M., Rodriguez-Frade, J.M., Balomenos, D. and Martinez, A.C. (2004) Leukocyte Attraction through the CCR5 Receptor Controls Progress from Insulitis to Diabetes in Non-Obese Diabetic Mice. European Journal of Immunology, 34, 548-557.

[22] Zhang, Y., Bandala-Sanchez, E. and Harrison, L.C. (2012) Revisiting Regulatory T Cells in Type 1 Diabetes. Current Opinion in Endocrinology, Diabetes, and Obesity, 19, 271-278.

[23] Li, S.J. and Hochstrasser, M. (1999) A New Protease Re-quired for Cell-Cycle Progression in Yeast. Nature, 398, 246- 251.

[24] Gill, G. (2004) SUMO and Ubiquitin in the Nucleus: Different Functions, Similar Mechanisms? Genes & Development, 18, 2046-2059.

[25] Li, M., Guo, D., Isales, C.M., Eizirik, D.L., Atkinson, M., She, J.X. and Wang, C.Y. (2005) SUMO Wrestling with Type 1 Diabetes. Journal of Molecular Medicine, 83, 504-513.

[26] Guo, D., Li, M., Zhang, Y., Yang, P., Eckenrode, S., Hopkins, D., Zheng, W., Purohit, S., Podolsky, R.H., Muir, A., Wang, J., Dong, Z., Brusko, T., Atkinson, M., Pozzilli, P., Zeidler, A., Raffel, L.J., Jacob, C.O., Park, Y., Serrano-Rios, M., Larrad, M.T., Zhang, Z., Garchon, H.J., Bach, J.F., Rotter, J.I., She, J.X. and Wang, C.Y. (2004) A Functional Variant of SUMO4, a New I Kappa B Alpha Modifier, Is Associated with Type 1 Diabetes. Nature Genetics, 36, 837-841.

[27] Aribi, M. (2008) Candidate Genes Implicated in Type 1 Diabetes Susceptibility. Current Diabetes Reviews, 4, 110- 121.

[28] Wang, C.Y., Podolsky, R. and She, J.X. (2006) Genetic and Functional Evidence Supporting SUMO4 as a Type 1 Diabetes Susceptibility Gene. Annals of the New York Academy of Sciences, 1079, 257-267.

[29] Hayashi, T. and Faustman, D. (1999) NOD Mice Are Defective in Proteasome Production and Activation of NF-kap- paB. Molecular and Cellular Biology, 19, 8646-8659.

[30] Mabb, A.M. and Miyamoto, S. (2007) SUMO and NF-kappaB Ties. Cellular and Molecular Life Sciences, 64, 1979- 1996.

[31] Huang, T.T., Wuerzberger-Davis, S.M., Wu, Z.H. and Miyamoto, S. (2003) Sequential Modification of NEMO/IKK- gamma by SUMO-1 and Ubiquitin Mediates NF-kappaB Activation by Genotoxic Stress. Cell, 115, 565-576.

[32] Lee, M.H., Mabb, A.M., Gill, G.B., Yeh, E.T. and Miyamoto, S. (2011) NF-kappaB Induction of the SUMO Protease SENP2: A Negative Feedback Loop to Attenuate Cell Survival Response to Genotoxic Stress. Molecular Cell, 43, 180- 191.