瘦素研究的最新进展和科学意义
Recent Progress in the Study of Leptin and Its Scientific Significance

作者: 高文荣 , 张 浩 , 姜文秀 , 朱万龙 :云南师范大学生命科学学院,昆明;

关键词: 瘦素瘦素抵抗瘦素受体信号通路肥胖Leptin Leptin Resistance Leptin Receptor Signal Path Obesity

摘要: 瘦素主要是由脂肪细胞分泌的一种蛋白质,与机体摄食、能量代谢、脂肪存储等的调控密切相关。目前,瘦素抵抗作为肥胖发生的一个重要危险因素已经得到公认,但具体清晰的作用机制仍未阐明,仅有瘦素受体突变、瘦素转运、瘦素信号抑制、血管内缺陷、转换缺陷等各种假说。全球的研究者正试图以这些假说为基础探讨肥胖的发生机制,进而攻克肥胖。本文对瘦素及其受体的基因表达和分子结构做了简单介绍,分析了瘦素参与的JAK/STATRasMAPK信号通路。重点探讨了瘦素抵抗机制的可能通路,以期对肥胖的瘦素抵抗机制研究有一定的参考意义。

Abstract: Leptin is a protein mainly secreted by the lipocyte, which is related to the regulation of food intake, energy expenditure and fat storage closely. Currently, the theory that leptin resistance is a primary risk factor for obesity has been accepted widely. But the clear mechanism has not been clarified yet. The occurrence of leptin resistance may be related to some hypotheses, such as leptin receptor mutation, leptin transshipment, leptin signal suppression, vascular defects and conversion defects. The researchers from all over the world are trying to discover the mechanism based on these hypotheses and are expecting to cure the obesity completely. This review 1) briefly introduces the gene expression and the molecular structure of leptin and leptin receptor; 2) analyzes the signal transduction of leptin such as JAK/STAT, Ras and MAPK; 3) summarizes the access of leptin resistance. Maybe the work will have the certain reference value to the obesity research in the mechanisms of leptin resistance.

文章引用: 高文荣 , 张 浩 , 姜文秀 , 朱万龙 (2014) 瘦素研究的最新进展和科学意义。 生物过程, 4, 1-10. doi: 10.12677/BP.2014.41001

参考文献

[1] Fuentest, A.I. (2009) Leptin receptor 170 KDa (OB2R170) protein expression is reduced in obese human skeletal muscle: A potential mechanism of leptin resistance. Exphysiol, 45, 48-55.

[2] Lund, I.K., Hansea, J.A., Andersen, H.S., et al. (2005) Mechanism of protein tyrosine phosphatase 1B-mediated inhibi- tion of leptin signalling. Journal of Molecular Endocrinology, 34, 339-351.

[3] Zabolotny, J.M. and Bence-hanulec, K.K. (2002) PTP1B Regulates Leptin Signal Transduction in Vivo. Developmental Cell, 2, 489-495.

[4] White, C., Whittington, A., Barbes, M.J., et al. (2009) HF diets increase hypothalamic PTP1B and induce leptin resis- tance through both leptin-dependent and independent mechanisms. American Journal of Physiology. Endocrinology and Metabolism, 296, E291-E299.

[5] Steinberg, G.R. and Dyck, D.J. (2000) Development of leptin resistance in rat soleus muscle in response to high-fat diets. American Journal of Physiology. Endocrinology and Metabolism, 279, 1374-1382.

[6] Ahima, R.S. and Flier, J.S. (2000) Leptin. Annual Review of Physiology, 62, 413-437.

[7] Sinsa, M.K. (1997) Human leptin: The hormone of adipose tissue. European Journal of Endocrinology, 136, 461-464.

[8] Considinc, R.V., Sinha, M.K., Heiman, M.L., et al. (1996) Serum immunoreactive Leptin comcentrations in normal- weight and obese humans. The New England Journal of Medicine, 334, 292-295.

[9] Cohen, S.L. (1996) Human leptin characterization. Nature, 38, 85-89.

[10] 赵小刚, 谭支良, 汤少勋 (2006) 瘦素的生物学功能及其调控. 华北农学报, 21, 186-190.

[11] Ogawa, Y (1995) Molecular cloning of rat obese cDNA and augmented gene expression in genetically obese Zucker fatty (fa/ fa) rats. Journal of Clinical Investigation, 96, 1647-1652.

[12] Fain, J.N., Tichansky, I.D.S. and Madan, A.K. (2005) Trans forming growth factor beta1 release by human adipose tissue is enhanced in obesity. Metabolism, 54, 1546-1553.

[13] Vanrossum, C.T (2003) Variation in the leptin receptor gene, leptin, and weight gain in young dutch adults. Obesity Research, 11, 377-386.

[14] Paul, C. (2002) Role for stearoyl-CoA desaturase-1 in leptin mediated weight loss. Science, 297, 240-243.

[15] 邬楠, 谭焕然 (2004) 瘦素受体的分子生物学研究进展. 大连医科大学学报, 2, 148-150.

[16] Tena-Sempere, M., Pinliaa, L., Gonzalea, L.C., et al. (2000) In vitro pituitary and testicular effects of leptin-related synthetic peptide leptin(116-130) amide involve actions both similar and distinct to those of the native leptin molecule in the adult rat. European Journal of Endocrinology, 142, 406-410.

[17] Kleok, C., Haq, A.K., Dunn, S.L., et al. (2002) Regulation of Jak kinases by intracellular leptin receptor sequences. Journal of Biological Chemistry, 277, 41547-41555

[18] Bendinelli, P., Maroni, P., Pecori, G.F., et al. (2000) Leptin activates Stat3, Stat1and AP 21 in mouse adipose tissue. Molecular and Cellular Endocrinology, 168, 37-45.

[19] 郭启煜 (2002) 瘦素的信号转导机制. 国外医学: 分子生物学分册, 2, 105-108

[20] Hansen, J.A., Lindberg, K., Hilton, D.J., et al. (1999) Mechanism of inhibition of growth hormone receptors ignaling by suppressor of cytokine signaling proteins. Molecular Endocrinology, 13, 1832-1837.

[21] Kaszubska, W., Falls, H.D., Schaefer, V.G., et al. (2002) Protein tyrosine phospha-tase 1B negatively regulates leptin signaling in a hypothalamic cell line. Molecular and Cellular Endocrinology, 195, 109-114.

[22] Chung, C.D., Liao, J., Liu, B., et al. (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science, 278, 1803-1805.

[23] Ellacott, K.L. and Cone, R.D. (2004) The central melanocortin system and the integration of short and long term regu- lators of energy homeostasis. Recent Progress in Hormone Research, 59, 395-401.

[24] 贾弘褆 (2007) 《生物化学》第三版. 北京大学医学出版社, 北京, 442-443.

[25] Fujioka, Y., Matozaki, T., Noguchit, et al. (1996) A novel membrane glycoprotein, SHPS21, that binds the SH22 do-main-containing proteintyros inephosphatase SHP2 in response to mitogens and cell adhesion. Molecular and Cellular Biology, 16, 6887-6892.

[26] Carpenter, L.R., Farruggell, T.J., Symes, A., et al. (1998) Enhancing leptin response by preventing SH22 containing phosphatase -interaction with Ob receptor. Proceedings of the National Academy of Sciences of the United States of America, 95, 6061-6066.

[27] Minokoshi, Y., KimI, Y.B., Peroni, O.D., et al. (2002) Leptin stimulates fatty acidoxidation by activating AMP acti- vated protein kinase. Nature, 415, 339-343.

[28] Unger, R.H., Yhou, Y.T. and Orci, L. (1999) Regulation of fatty acid homeostasis incells: Novel role of leptin. Pro- ceedings of the National Academy of Sciences of the United States of America, 96, 2327-2332.

[29] Qiu, J., Ogus, S., Mozihun, K., et al. (2001) Leptin-deficient mice backcrossed to the BALB/cJ genetic background have reduced adiposity, enhanced fertility, normal body temperature, and severe diabetes. Endocrinology, 142, 3421- 3425.

[30] Caro, J.F., Sinha, M.K., Kolaczynski, J.W., et al. (1996) Leptin: The tale of an obesity gene. Diabetes, 45, 1455-1462.

[31] Lanlou, N., Clement, K., Carel, J.C., et al. (2000) Soluble leptin receptor in serum of subjects with complete resistance to leptin. Diabetes, 49, 1347-1352.

[32] Mark, A.L., Correia, M.L., Rahmouni, K., et al. (2002) Selective leptin resistance: A new concept in leptin physiology with cardiovas cularimp lications. Journal of Hypertension, 20, 1245-1250.

[33] Halaas, J.L., Boozer, C., Blair-west, J., et al. (1997) Physiological response to Long-term peripheral and central leptin infusion in lean and obese mice. Proceedings of the National Academy of Sciences of the United States of America, 94, 8878-8883.

[34] El-Haschimi, K., Pierroz, D.D., Hilemam, S.M., et al. (2000) Two defects contribute to hypothalamic leptin resistance in mice with diet induced obesity. Journal of Clinical Investigation, 105, 1827-1832.

[35] Rahmouni, K., Haynes, W.G., Morgan, D.A., et al. (2002) Selective resistance to central neural administration of leptin in agouti obese mice. Hypertension, 39, 486-490.

[36] Boado, R.J., Golden, P.L., Levin, N., et al. (1998) Up-regulation of blood-brain barrier short form leptin receptor gene products in rats fed a high fat diet. Journal of Neurochemistry, 71, 1761-1763.

[37] Luheshi, G.N., Gardner, J.D., Rushforth, D.A., et al. (1999) Leptin actions on food intake and body temperature are mediated by IL21. Proceedings of the National Academy of Sciences of the United States of America, 96, 7047-7052.

[38] Gutierrsz, E., Banks, W. and Kastin, A. (1994) Blood-borne interleukin-1 receptor antagonist crosses the blood-brain barrier. Journal of Neuroimmunology, 55, 153-160.

[39] Shintani, M., Ogawa, Y., Bihara, K., et al. (2001) Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic pep tide that antagonizes leptin action through the activation of hypothalamic neuropep tide Y/Y1 receptor pathway. Diabetes, 50, 227-232.

[40] Bjrbaek, C., El-haschimi, K., Frantz, J.D., et al. (1999) The role of SOCS-3 in leptin signaling and leptin resistance. Journal of Biological Chemistry, 274, 30059-30065.

[41] Dunn, S., Bjornholm, M., Bates, S.H., et al. (2005) Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and suppressor of cytokine signaling 3. Molecular Endocrinology, 19, 925-938.

[42] Howard, J.K., Cav, B.J., Oksanen, L.J., et al. (2004) Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nature Medicine, 10, 734-738.

[43] Mori, H., Hanada, R., Hanada, T., et al. (2004) Socs 3 deficiency in the brain elevates leptin sensitivity and confers re- sistance to diet-induced obesity. Nature Medicine, 10, 739-743.

[44] Steinberg, G.R., Mcainch, J., Chen, M.B., et al. (2006) The suppressor of cytokine signaling 3 inhibits leptin activation of AMP-kinase in cultured skeletal muscle of obese humans. Journal of Clinical Endocrinology and Metabolism, 91, 3592-3594.

[45] Masaki, T., Yoshimaytsu, H., Chiba, S., et al. (2001) Targeted disruption of histamine H1-receptor attenuates regula- tory effects of leptin on feeding, adiposity, and UCP family in mice. Diabetes, 50, 385-391.

分享
Top