医学研究与教育 ›› 2023, Vol. 40 ›› Issue (4): 1-10.DOI: 10.3969/j.issn.1674-490X.2023.04.001
• 基础医学 • 下一篇
周向阳,吴迪,米甜,李文娟
收稿日期:
2023-05-19
出版日期:
2023-08-25
发布日期:
2023-08-25
通讯作者:
李文娟(1977—),女,甘肃静宁人,教授,博士,硕士生导师,主要从事肿瘤代谢的研究。E-mail: liwenjuan@hbu.edu.cn
作者简介:
周向阳(1997—),男,山西大同人,在读硕士,主要从事肿瘤代谢及化学预防的研究。 E-mail: zxy9708@163.com
基金资助:
Received:
2023-05-19
Online:
2023-08-25
Published:
2023-08-25
摘要: 瘦素(leptin)是一种由白色脂肪细胞分泌的激素,作为脂肪组织和中枢神经系统网络联系的外周信号,影响人体的摄食、能量平衡、内分泌和免疫功能等。通过分析总结瘦素及其受体(leptin receptor,LEPR)分子结构和细胞内分布, 对其在调节脂代谢、炎症与免疫、创伤愈合及肿瘤发展等方面的研究进展进行综述。
中图分类号:
周向阳,吴迪,米甜,李文娟. 瘦素的生物学作用及其相关机制研究进展[J]. 医学研究与教育, 2023, 40(4): 1-10.
[1] ZHANG Y, PROENCA R, MAFFEI M, et al. Positional cloning of the mouse obese gene and its human homologue[J]. Nature, 1994, 372(6505): 425-432. DOI: 10.1038/372425a0. [2] KELESIDIS T, KELESIDIS I, CHOU S, et al. Narrative review: the role of leptin in human physiology: emerging clinical applications[J]. Ann Intern Med, 2010, 152(2): 93-100. DOI: 10.7326/0003-4819-152-2-201001190-00008. [3] KOHLSDORF K, NUNZIATA A, FUNCKE J B, et al. Early childhood BMI trajectories in monogenic obesity due to leptin, leptin receptor, and melanocortin 4 receptor deficiency[J]. Int J Obes(Lond), 2018, 42(9): 1602-1609. DOI: 10.1038/s41366-018-0049-6. [4] KLINE A D, BECKER G W, CHURGAY L M, et al. Leptin is a four-helix bundle: secondary structure by NMR[J]. FEBS Lett, 1997, 407(2): 239-242. DOI: 10.1016/s0014-5793(97)00353-0. [5] REHMAN K, AKASH M S H, ALINA Z. Leptin: a new therapeutic target for treatment of diabetes mellitus[J]. J Cell Biochem, 2018, 119(7): 5016-5027. DOI: 10.1002/jcb.26580. [6] PEREIRA S, CLINE D L, GLAVAS M M, et al. Tissue-specific effects of leptin on glucose and lipid metabolism[J]. Endocr Rev, 2021, 42(1): 1-28. DOI: 10.1210/endrev/bnaa027. [7] MARTÍNEZ-SÁNCHEZ N. There and back again: leptin actions in white adipose tissue[J]. Int J Mol Sci, 2020, 21(17): 6039. DOI: 10.3390/ijms21176039. [8] STEPIEN M, ROSNIAK-BAK K, PARADOWSKI M, et al. Waist circumference, ghrelin and selected adipose tissue-derived adipokines as predictors of insulin resistance in obese patients: preliminary results[J]. Med Sci Monit, 2011, 17(11): PR13-PR18. DOI: 10.12659/msm.882030. [9] CARO J F, KOLACZYNSKI J W, NYCE M R, et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance[J]. Lancet, 1996, 348(9021): 159-161. DOI: 10.1016/s0140-6736(96)03173-x. [10] FAOUZI M, LESHAN R, BJÖRNHOLM M, et al. Differential accessibility of circulating leptin to individual hypothalamic sites[J]. Endocrinology, 2007, 148(11): 5414-5423. DOI: 10.1210/en.2007-0655. [11] MURPHY K T, SCHWARTZ G J, NGUYEN N L, et al. Leptin-sensitive sensory nerves innervate white fat[J]. Am J Physiol Endocrinol Metab, 2013, 304(12): E1338-E1347. DOI: 10.1152/ajpendo.00021.2013. [12] GHADGE A A, KHAIRE A A. Leptin as a predictive marker for metabolic syndrome[J]. Cytokine, 2019, 121: 154735. DOI: 10.1016/j.cyto.2019.154735. [13] BERGER C, KLÖTING N. Leptin receptor compound heterozygosity in humans and animal models[J]. Int J Mol Sci, 2021, 22(9): 4475. DOI: 10.3390/ijms22094475. [14] ZABEAU L, WAUMAN J, DAM J, et al. A novel leptin receptor antagonist uncouples leptin's metabolic and immune functions[J]. Cell Mol Life Sci, 2019, 76(6): 1201-1214. DOI: 10.1007/s00018-019-03004-9. [15] MOHARANA K, ZABEAU L, PEELMAN F, et al. Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins[J]. Structure, 2014, 22(6): 866-877. DOI: 10.1016/j.str.2014.04.012. [16] TSIRIGOTAKI A, DANSERCOER A, VERSCHUEREN K H G, et al. Mechanism of receptor assembly via the pleiotropic adipokine Leptin[J]. Nat Struct Mol Biol, 2023, 30(4): 551-563. DOI: 10.1038/s41594-023-00941-9. [17] ZHANG F M, CHEN Y Y, HEIMAN M, et al. Leptin: structure, function and biology[J]. Vitam Horm, 2005, 71: 345-372. DOI: 10.1016/S0083-6729(05)71012-8. [18] SÉRON K, COUTURIER C, BELOUZARD S, et al. Endospanins regulate a postinternalization step of the leptin receptor endocytic pathway[J]. J Biol Chem, 2011, 286(20): 17968-17981. DOI: 10.1074/jbc.M111.224857. [19] D'SOUZA A M, NEUMANN U H, GLAVAS M M, et al. The glucoregulatory actions of leptin[J]. Mol Metab, 2017, 6(9): 1052-1065. DOI: 10.1016/j.molmet.2017.04.011. [20] TU L L, FUKUDA M, TONG Q C, et al. The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis[J]. Cell Biosci, 2022, 12(1): 71. DOI: 10.1186/s13578-022-00799-2. [21] DUQUENNE M, FOLGUEIRA C, BOUROUH C, et al. Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function[J]. Nat Metab, 2021, 3(8): 1071-1090. DOI: 10.1038/s42255-021-00432-5. [22] LEE Y H, MAGKOS F, MANTZOROS C S, et al. Effects of leptin and adiponectin on pancreatic β-cell function[J]. Metabolism, 2011, 60(12): 1664-1672. DOI: 10.1016/j.metabol.2011.04.008. [23] BOUCSEIN A, KAMSTRA K, TUPS A. Central signalling cross-talk between insulin and leptin in glucose and energy homeostasis[J]. J Neuroendocrinol, 2021, 33(4): e12944. DOI: 10.1111/jne.12944. [24] LI R J W, ZHANG S Y, LAM T K T. Interaction of glucose sensing and leptin action in the brain[J]. Mol Metab, 2020, 39: 101011. DOI: 10.1016/j.molmet.2020.101011. [25] ZHAO S G, ZHU Y, SCHULTZ R D, et al. Partial leptin reduction as an insulin sensitization and weight loss strategy[J]. Cell Metab, 2019, 30(4): 706-719. DOI: 10.1016/j.cmet.2019.08.005. [26] CHINOOKOSWONG N, WANG J L, SHI Z Q. Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat[J]. Diabetes, 1999, 48(7): 1487-1492. DOI: 10.2337/diabetes.48.7.1487. [27] NEUMANN U H, DENROCHE H C, MOJIBIAN M, et al. Insulin knockout mice have extended survival but volatile blood glucose levels on leptin therapy[J]. Endocrinology, 2016, 157(3): 1007-1012. DOI: 10.1210/en.2015-1890. [28] WANG P, LOH K H, WU M, et al. A leptin-BDNF pathway regulating sympathetic innervation of adipose tissue[J]. Nature, 2020, 583(7818): 839-844. DOI: 10.1038/s41586-020-2527-y. [29] VILLANUEVA-CARMONA T, CEDÓL, MADEIRA A, et al. SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression[J]. Cell Metab, 2023, 35(4): 601-619. DOI: 10.1016/j.cmet.2023.03.004. [30] JAUBERT A M, PENOT G, NIANG F, et al. Rapid nitration of adipocyte phosphoenolpyruvate carboxykinase by leptin reduces glyceroneogenesis and induces fatty acid release[J]. PLoS One, 2012, 7(7): e40650. DOI: 10.1371/journal.pone.0040650. [31] PARK Y M, MYERS M, VIEIRA-POTTER V J. Adipose tissue inflammation and metabolic dysfunction: role of exercise[J]. Mo Med, 2014, 111(1): 65-72. [32] PALHINHA L, LIECHOCKI S, HOTTZ E D, et al. Leptin induces proadipogenic and proinflammatory signaling in adipocytes[J]. Front Endocrinol(Lausanne), 2019, 10: 841. DOI: 10.3389/fendo.2019.00841. [33] VUOLTEENAHO K, KOSKINEN A, KUKKONEN M, et al. Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage: mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production[J]. Mediators Inflamm, 2009, 2009: 345838. DOI: 10.1155/2009/345838. [34] ACEDO S C, GAMBERO S, CUNHA F G, et al. Participation of leptin in the determination of the macrophage phenotype: an additional role in adipocyte and macrophage crosstalk[J]. In Vitro Cell Dev Biol Anim, 2013, 49(6): 473-478. DOI: 10.1007/s11626-013-9629-x. [35] LA CAVA A. Proinflammatory activities of leptin in non-autoimmune conditions[J]. Inflamm Allergy Drug Targets, 2012, 11(4): 298-302. DOI: 10.2174/187152812800959031. [36] LUAN B, GOODARZI M O, PHILLIPS N G, et al. Leptin-mediated increases in catecholamine signaling reduce adipose tissue inflammation via activation of macrophage HDAC4[J]. Cell Metab, 2014, 19(6): 1058-1065. DOI: 10.1016/j.cmet.2014.03.024. [37] GAN L, LIU Z, FENG F, et al. Foxc2 coordinates inflammation and browning of white adipose by leptin-STAT3-PRDM16 signal in mice[J]. Int J Obes(Lond), 2018, 42(2): 252-259. DOI: 10.1038/ijo.2017.208. [38] KIGUCHI N, MAEDA T, KOBAYASHI Y, et al. Leptin enhances CC-chemokine ligand expression in cultured murine macrophage[J]. Biochem Biophys Res Commun, 2009, 384(3): 311-315. DOI: 10.1016/j.bbrc.2009.04.121. [39] SOUZA-ALMEIDA G, D'AVILA H, ALMEIDA P E, et al. Leptin mediates in vivo neutrophil migration: involvement of tumor necrosis factor-alpha and CXCL1[J]. Front Immunol, 2018, 9: 111. DOI: 10.3389/fimmu.2018.00111. [40] PROCACCINI C, DE ROSA V, GALGANI M, et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness[J]. Immunity, 2010, 33(6): 929-941. DOI: 10.1016/j.immuni.2010.11.024. [41] PROCACCINI C, DE ROSA V, GALGANI M, et al. Leptin-induced mTOR activation defines a specific molecular and transcriptional signature controlling CD4+ effector T cell responses[J]. J Immunol, 2012, 189(6): 2941-2953. DOI: 10.4049/jimmunol.1200935. [42] AMARILYO G, IIKUNI N, SHI F D, et al. Leptin promotes lupus T-cell autoimmunity[J]. Clin Immunol, 2013, 149(3): 530-533. DOI: 10.1016/j.clim.2013.09.002. [43] POEGGELER B, SCHULZ C, PAPPOLLA M A, et al. Leptin and the skin: a new frontier[J]. Exp Dermatol, 2010, 19(1): 12-18. DOI: 10.1111/j.1600-0625.2009.00930.x. [44] YUAN C, LIAO J, ZHENG L Y, et al. Current knowledge of leptin in wound healing: a collaborative review[J]. Front Pharmacol, 2022, 13: 968142. DOI: 10.3389/fphar.2022.968142. [45] ZHANG L, LI R, WU B H, et al. Leptin activates the JAK/STAT pathway to promote angiogenesis in RF/6A cells in vitro[J]. Int J Ophthalmol, 2022, 15(4): 554-559. DOI: 10.18240/ijo.2022.04.05. [46] TADOKORO S, IDE S, TOKUYAMA R, et al. Leptin promotes wound healing in the skin[J]. PLoS One, 2015, 10(3): e0121242. DOI: 10.1371/journal.pone.0121242. [47] UMEKI H, TOKUYAMA R, IDE S, et al. Leptin promotes wound healing in the oral mucosa[J]. PLoS One, 2014, 9(7): e101984. DOI: 10.1371/journal.pone.0101984. [48] TANIGAWA T, WATANABE T, OTANI K, et al. Leptin promotes gastric ulcer healing via upregulation of vascular endothelial growth factor[J]. Digestion, 2010, 81(2): 86-95. DOI: 10.1159/000243719. [49] STALLMEYER B, KÄMPFER H, PODDA M, et al. A novel keratinocyte mitogen: regulation of leptin and its functional receptor in skin repair[J]. J Invest Dermatol, 2001, 117(1): 98-105. DOI: 10.1046/j.0022-202x.2001.01387.x. [50] GRÖSCHL M, TOPF H G, KRATZSCH J, et al. Salivary leptin induces increased expression of growth factors in oral keratinocytes[J]. J Mol Endocrinol, 2005, 34(2): 353-366. DOI: 10.1677/jme.1.01658. [51] 李培兵, 金宏, 刘佃辛, 等. 瘦素促进皮肤创伤大鼠胶原合成的实验研究[J]. 中国应用生理学杂志, 2011, 27(1):72-74,132. [52] KOVÁCS D, FAZEKAS F, OLÁH A, et al. Adipokines in the skin and in dermatological diseases[J]. Int J Mol Sci, 2020, 21(23): 9048. DOI: 10.3390/ijms21239048. [53] SŁABUSZEWSKA-JÓZ'WIAK A, LUKASZUK A, JANICKA-KOS'NIK M, et al. Role of leptin and adiponectin in endometrial cancer[J]. Int J Mol Sci, 2022, 23(10): 5307. DOI: 10.3390/ijms23105307. [54] EL-DEEB A M, FANSA H A, WAHBA O M. The expression of leptin in oral wound healing in diabetes mellitus: an experimental study[J]. Int J Health Sci(Qassim), 2018, 12(2): 22-25. [55] ZHAO J Z, LEE K, TOH H C, et al. Unravelling the role of obesity and lipids during tumor progression[J]. Front Pharmacol, 2023, 14: 1163160. DOI: 10.3389/fphar.2023.1163160. [56] AVGERINOS K I, SPYROU N, MANTZOROS C S, et al. Obesity and cancer risk: emerging biological mechanisms and perspectives[J]. Metabolism, 2019, 92: 121-135. DOI: 10.1016/j.metabol.2018.11.001. [57] ZHAO C R, WU M, ZENG N, et al. Cancer-associated adipocytes: emerging supporters in breast cancer[J]. J Exp Clin Cancer Res, 2020, 39(1): 156. DOI: 10.1186/s13046-020-01666-z. [58] FILALI-MOUNCEF Y, HUNTER C, ROCCIO F, et al. The ménage à trois of autophagy, lipid droplets and liver disease[J]. Autophagy, 2022, 18(1): 50-72. DOI: 10.1080/15548627.2021.1895658. [59] XU M, CAO F L, LI N Y, et al. Leptin induces epithelial-to-mesenchymal transition via activation of the ERK signaling pathway in lung cancer cells[J]. Oncol Lett, 2018, 16(4): 4782-4788. DOI: 10.3892/ol.2018.9230. [60] BOWERS L W, ROSSI E L, MCDONELL S B, et al. Leptin signaling mediates obesity-associated CSC enrichment and EMT in preclinical TNBC models[J]. Mol Cancer Res, 2018, 16(5): 869-879. DOI: 10.1158/1541-7786.MCR-17-0508. [61] THIAGARAJAN P S, ZHENG Q, BHAGRATH M, et al. STAT3 activation by leptin receptor is essential for TNBC stem cell maintenance[J]. Endocr Relat Cancer, 2017, 24(8): 415-426. DOI: 10.1530/ERC-16-0349. [62] GORRAB A, PAGANO A, AYED K, et al. Leptin promotes prostate cancer proliferation and migration by stimulating STAT3 pathway[J]. Nutr Cancer, 2021, 73(7): 1217-1227. DOI: 10.1080/01635581.2020.1792946. [63] CAO D X, LUO Y, QIN S L, et al. Metallopanstimulin-1(MPS-1)mediates the promotion effect of leptin on colorectal cancer through activation of JNK/c-Jun signaling pathway[J]. Cell Death Dis, 2019, 10(9): 655. DOI: 10.1038/s41419-019-1911-8. [64] CAMPO-VERDE-ARBOCCO F, LÓPEZ-LAUR J D, ROMEO L R, et al. Human renal adipose tissue induces the invasion and progression of renal cell carcinoma[J]. Oncotarget, 2017, 8(55): 94223-94234. DOI: 10.18632/oncotarget.21666. [65] AMJADI F, MEHDIPOOR R, ZARKESH-ESFAHANI H, et al. Leptin serves as angiogenic/mitogenic factor in melanoma tumor growth[J]. Adv Biomed Res, 2016, 5: 127. DOI: 10.4103/2277-9175.187005. [66] CHEN C, CHANG Y C, LIU C L, et al. Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway[J]. Endocr Relat Cancer, 2007, 14(2): 513-529. DOI: 10.1677/ERC-06-0027. [67] RIBATTI D, BELLONI A S, NICO B, et al. Leptin-leptin receptor are involved in angiogenesis in human hepatocellular carcinoma[J]. Peptides, 2008, 29(9): 1596-1602. DOI: 10.1016/j.peptides.2008.05.011. [68] KAUSHIK N, KIM S, SUH Y, et al. Proinvasive extracellular matrix remodeling for tumor progression[J]. Arch Pharm Res, 2019, 42(1): 40-47. DOI: 10.1007/s12272-018-1097-0. [69] GHASEMI A, HASHEMY S I, AGHAEI M, et al. Leptin induces matrix metalloproteinase 7 expression to promote ovarian cancer cell invasion by activating ERK and JNK pathways[J]. J Cell Biochem, 2018, 119(2): 2333-2344. DOI: 10.1002/jcb.26396. [70] STEFANOU N, PAPANIKOLAOU V, FURUKAWA Y, et al. Leptin as a critical regulator of hepatocellular carcinoma development through modulation of human telomerase reverse transcriptase[J]. BMC Cancer, 2010, 10: 442. DOI: 10.1186/1471-2407-10-442. |
[1] | 罗发梦,刘蓉,林威娜,张海燕,陶德智. 炎症性肠病患者延续性护理体验和需求的质性研究[J]. 医学研究与教育, 2023, 40(5): 66-71. |
[2] | 张静波, 史坚, 杨静云, 冉继鹏, 刘子腾, 张莎莎. 抗核抗体与主动脉壁间血肿发生的相关性分析[J]. 医学研究与教育, 2022, 39(5): 19-24. |
[3] | 朱健平,李运曼. Nrf2在缺血性脑损伤中的关键性作用[J]. 医学研究与教育, 2022, 39(2): 1-9. |
[4] | 位亚利,孙珵珵,王晓春. 血管拟态在乳腺癌中的研究进展[J]. 医学研究与教育, 2022, 39(2): 16-23. |
[5] | 罗发梦,刘蓉,张海燕. 炎症性肠病患者的药物管理研究进展[J]. 医学研究与教育, 2022, 39(2): 66-71. |
[6] | 黄新文,陈灵莉,程艺. 儿科规范化培训住院医师遗传代谢病教学情况分析[J]. 医学研究与教育, 2021, 38(5): 69-74. |
[7] | 周程艳,李倩,梁宇璇,国洪宾,赵盈秋. 两种动脉粥样硬化模型制备方法的比较[J]. 医学研究与教育, 2021, 38(1): 1-11. |
[8] | 宋天娇,高倩,卢丹丹,万莉,王佩. 血清脂蛋白(a)及脂肪因子瘦素在急性脑梗死中的诊断价值[J]. 医学研究与教育, 2021, 38(1): 32-36. |
[9] | 郝婕,张倩,王媛,徐俊荣. 体检人群脂肪肝患病率及危险因素[J]. 医学研究与教育, 2021, 38(1): 45-52. |
[10] | 李鹤飞, 王海波, 李伟, 史鸿云, 贾友超. 外周血ctDNA基因突变对早中期非小细胞肺癌患者的诊断效能分析[J]. 医学研究与教育, 2020, 37(6): 23-28. |
[11] | 柴素伟. 腹腔镜结直肠癌NOSES疗效分析以及对氧化应激、炎性反应的影响[J]. 医学研究与教育, 2020, 37(5): 31-35. |
[12] | 潘秀敏,张金立,闫红丽,李梦琳,郭敬如. 高选择性肾动脉分支阻断与全阻断下腹腔镜保留肾单位手术疗效及肾功能对比[J]. 医学研究与教育, 2020, 37(1): 30-35. |
[13] | 马继飞,侯烨,龙霏,赵博兰. 唐县2018年恶性肿瘤发病及死亡情况分析[J]. 医学研究与教育, 2020, 37(1): 60-64. |
[14] | 路潜,张力川,王玉洁,庄冰,孙艳. 头颈部恶性肿瘤患者放疗前营养风险与营养不良状况分析[J]. 医学研究与教育, 2019, 36(6): 54-62. |
[15] | 左彦波,贾娟,王红杰. 慢性肾脏病骨质疏松发病机制的研究进展[J]. 医学研究与教育, 2019, 36(4): 10-18. |
阅读次数 | ||||||
全文 |
|
|||||
摘要 |
|
|||||