瘦素信号转导与瘦素抵抗研究进展
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摘要
瘦素是由肥胖基因编码、脂肪组织分泌的一种肽类激素,瘦素与瘦素受体结合激活多种信号转导通路,发挥调节能量代谢和抑制食欲的作用。大多数肥胖患者体内存在瘦素抵抗现象,即瘦素水平增高但作用减弱或消失。瘦素抵抗发生机制与多种因素有关,目前尚未完全阐明,但其主要原因在于受体后信号转导障碍。因此,研究瘦素信号转导通路和瘦素抵抗对提出克服瘦素抵抗策略从而防治肥胖具有重要意义。
Leptin is a peptide hormone encoded by fat gene and secreted by adipose tissue. Leptin binds to leptin receptor and activates a variety of signal transduction pathways, playing a role in regulating energy metabolism and appetite suppression. Leptin resistance is present in most obese patients, in which leptin level increased but effect diminished or disappeared. The mechanism of leptin resistance is related to many factors and not fully elucidated now, but its main reason is the post-receptor signal transduction disorder. Therefore, the study on leptin signaling pathways and leptin resistance is important to propose strategies to overcome leptin resistance and thus to prevent and control obesity.
Leptin is a peptide hormone encoded by fat gene and secreted by adipose tissue. Leptin binds to leptin receptor and activates a variety of signal transduction pathways, playing a role in regulating energy metabolism and appetite suppression. Leptin resistance is present in most obese patients, in which leptin level increased but effect diminished or disappeared. The mechanism of leptin resistance is related to many factors and not fully elucidated now, but its main reason is the post-receptor signal transduction disorder. Therefore, the study on leptin signaling pathways and leptin resistance is important to propose strategies to overcome leptin resistance and thus to prevent and control obesity.
引文
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[27]Bjorbak C,Lavery HJ,Bates SH,et al.SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985[J].Journal of Biological Chemistry,2000,275(51):40649-40657.
[28]Zhou Y,Rui L.Leptin signaling and leptin resistance[J].Frontiers of Medicine,2013,7(2):207-222.
[29]Quan W,Kim HK,Moon EY,et al.Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response[J].Endocrinology,2012,153(4):1817-1826.
[30]Kaushik S,Rodriguez-Navarro JA,Arias E,et al.Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance[J].Cell Metabolism,2011,14(2):173-183.
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[33]Zhang X,Zhang G,Zhang H,et al.Hypothalamic IKKβ/NF-κBand ER stress link overnutrition to energy imbalance and obesity[J].Cell,2008,135(1):61-73.
[34]Murakami T,Iida M,Shima K.Dexamethasone regulates obese expression in isolated rat adipocytes[J].Biochemical and Biophysical Research Communications,1995,214(3):1260-1267.
[35]Kimura M,Tateishi N,Shiota T,et al.Long-term exercise downregulates leptin receptor mRNA in the arcuate nucleus[J].Neuroreport,2004,15(4):713-716.
[36]Tan Y,Chen WH,Guo L.Mechanism of exercise and diet interventions on central posterior rreceptor signaling of leptin resistance rats[J].China Sport Science,2011,31:57-66.
[37]Bj?rnholm M,Münzberg H,Leshan RL,et al.Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function[J].Journal of Clinical Investigation,2007,117(5):1354-1360.
[38]Bai X,Liu Z,Wang Y,et al.Down-regulation of suppressor of cytokines signaling 3 expression in hypothalamus attenuates highfat diet-induced obesity in rats[J].Chin J End Met,2012,28:63-67.
[39]Elchebly M,Payette P,Michaliszyn E,et al.Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene[J].Science,1999,283(5407):1544-1548.
[40]Bhattarai BR,Kafle B,Hwang JS,et al.Novel thiazolidinedione derivatives with anti-obesity effects:dual action as PTP1Binhibitors and PPAR-γactivators[J].Bioorganic and Medicinal Chemistry Letters,2010,20(22):6758-6763.
[41]Yu Y,Wu Y,Szabo A,et al.Teasaponin reduces inflammation and central leptin resistance in diet-induced obese male mice[J].Endocrinology,2013,154(9):3130-3140.
[42]Aubert G,Mansuy V,Voirol MJ,et al.The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression[J].Metabolism Clinical and Experimental,2011,60(3):327-334.
[43]Tam J,Cinar R,Liu J,et al.Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance[J].Cell Metabolism,2012,16(2):167-179.
[44]Mattace RG,Santoro A,Russo R,et al.Palmitoylethanolamide prevents metabolic alterations and restores leptin sensitivity in ovariectomized rats[J].Endocrinology,2014,155(4):1291-1301.
[45]Banks WA,Dipalma CR,Farrell CL.Impaired transport of leptin across the blood-brain barrier in obesity[J].Peptides,1999,20(11):1341-1345.
[46]Hsuchou H,Mishra PK,Kastin AJ,et al.Saturable leptin transport across the BBB persists in EAE mice[J].Journal of Molecular Neuroscience Mn,2013,51(2):364-370.
[47]Dietrich MO,Spuch C,Antequera D,et al.Megalin mediates the transport of leptin across the blood-CSF barrier[J].Neurobiology of Aging,2008,29(6):902-912.
[48]Yi X,Yuan D,Farr SA,et al.Pluronic modified leptin with increased systemic circulation,brain uptake and efficacy for treatment of obesity[J].Journal of Controlled Release,2014,191(15):34-46.
[49]Elinav E,Nivspector L,Katz M,et al.Pegylated leptin antagonist is a potent orexigenic agent:preparation and mechanism of activity[J].Endocrinology,2009,150(7):3083-3091.
[50]Hukshorn CJ,van Dielen FM,Buurman WA,et al.The effect of pegylated recombinant human leptin(PEG-OB)on weight loss and inflammatory status in obese subjects[J].International Journal of Obesity and Related Metabolic Disorders Journal of the International Association for the Study of Obesity,2002,26(4):504-509.
[51]Hosoi T,Miyahara T,Kayano T,et al.Fluvoxamine attenuated endoplasmic reticulum stress-induced leptin resistance[J].Frontiers in Endocrinology,2012,3:12.
[52]Hosoi T,Yamaguchi R,Noji K,et al.Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress[J].Embo Molecular Medicine,2014,6(3):335-346.
[2]Considine RV,Sinha MK,Heiman ML,et al.Serum immunoreactive-leptin concentrations in normal-weight and obese humans[J].New England Journal of Medicine,1996,334(5):292-295.
[3]Friedman JM,Halaas JL.Leptin and the regulation of body weight in mammals[J].Nature,1998,395(6704):763-770.
[4]Król E,Speakman JR.Regulation of body mass and adiposity in the field vole,Microtus agrestis:a model of leptin resistance[J].Journal of Endocrinology,2007,192(2):271-278.
[5]Rillamas-Sun E,Lacroix AZ,Waring ME,et al.Obesity and lateage survival without major disease or disability in older women[J].JAMA Internal Medicine,2014,174(1):98-106.
[6]Gorska E,Popko K,Stelmaszczyk-Emmel A,et al.Leptin receptors[J].European Journal of Medical Research,2010,15Suppl 2(S2):50-54.
[7]Banks AS,Davis SM,Bates SH,et al.Activation of downstream signals by the long form of the leptin receptor[J].Journal of Biological Chemistry,2000,275(19):14563-14572.
[8]Jr DJ,Fraza OR,Elias CF.The PI3K signaling pathway mediates the biological effects of leptin[J].Arquivos Brasileiros De Endocrinologia E Metabologia,2010,54(7):591-602.
[9]Zhao AZ,Huan JN,Gupta S,et al.A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding[J].Nature Neuroscience,2002,5(8):727-728.
[10]Sahu A.Intracellular leptin-signaling pathways in hypothalamic neurons:the emerging role of phosphatidylinositol-3 kinasephosphodiesterase-3B-cAMP pathway[J].Neuroendocrinology,2011,93(4):201-210.
[11]Cota D,Proulx K,Smith KA,et al.Hypothalamic mTOR signaling regulates food intake[J].Science,2006,312(5775):927-930.
[12]Cota D,Matter EK,Woods SC,et al.The role of hypothalamic mammalian target of rapamycin complex 1 signaling in dietinduced obesity[J].Journal of Neuroscience the Official Journal of the Society for Neuroscience,2008,28(28):7202-7208.
[13]Blouet C,Ono H,Schwartz GJ.Mediobasal hypothalamic p70 S6kinase 1 modulates the control of energy homeostasis[J].Cell Metabolism,2008,8(6):459-467.
[14]李晓环,邹宁.瘦素信号转导与瘦素抵抗研究进展[J].中国儿童保健杂志,2009,17(2):179-180.
[15]Zhang EE,Chapeau E,Hagihara K,et al.Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism[J].Proceedings of the National Academy of Sciences of the United States of America,2004,101(45):16064.
[16]Kamal R,Sigmund CD,Haynes WG,et al.Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin[J].Diabetes,2009,58(3):536-542.
[17]Minokoshi Y,Alquier T,Furukawa N,et al.AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus[J].Nature,2004,428(6982):569-574.
[18]Gao S,Kinzig KP,Aja S,et al.Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake[J].Proceedings of the National Academy of Sciences of the United States of America,2007,104(44):17358-17363.
[19]Caro JF,Kolaczynski JW,Nyce MR,et al.Decreased cerebrospinal-fluid/serum leptin ratio in obesity:a possible mechanism for leptin resistance[J].Lancet,1996,348(9021):159-161.
[20]Schwartz MW,Peskind E,Raskind M,et al.Cerebrospinal fluid leptin levels:relationship to plasma levels and to adiposity in humans[J].Nature Medicine,1996,2(5):589-593.
[21]mYERS MGJr,Heymsfield SB,Haft C,et al.Challenges and opportunities of defining clinical leptin resistance[J].Cell Metabolism,2012,15(2):150-156.
[22]Yu MH,Kang GM,Byun K,et al.Leptin-promoted cilia assembly is critical for normal energy balance[J].Journal of Clinical Investigation,2014,124(5):2193-2197.
[23]Heek MV,Compton DS,France CF,et al.Diet-induced obese mice develop peripheral,but not central,resistance to leptin[J].Journal of Clinical Investigation,1997,99(3):385-390.
[24]Caro JF,Sinha MK,Kolaczynski JW,et al.Leptin:the tale of an obesity gene[J].Diabetes,1996,45(11):1455-1462.
[25]Qiu J,Ogus S,Mounzih K,et al.Leptin-deficient mice backcrossed to the BALB/cJ genetic background have reduced adiposity,enhanced fertility,normal body temperature,and severe diabetes[J].Endocrinology,2001,142(8):3421-3425.
[26]丁文玲,刘长云,宋茂媛,等.瘦素抵抗及其受体基因变异对单纯性肥胖患儿脂代谢的影响[J].中华实用儿科临床杂志,2012,27(7):492-494.
[27]Bjorbak C,Lavery HJ,Bates SH,et al.SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985[J].Journal of Biological Chemistry,2000,275(51):40649-40657.
[28]Zhou Y,Rui L.Leptin signaling and leptin resistance[J].Frontiers of Medicine,2013,7(2):207-222.
[29]Quan W,Kim HK,Moon EY,et al.Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response[J].Endocrinology,2012,153(4):1817-1826.
[30]Kaushik S,Rodriguez-Navarro JA,Arias E,et al.Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance[J].Cell Metabolism,2011,14(2):173-183.
[31]Ron D,Walter P.Signal integration in the endoplasmic reticulum unfolded protein response[J].Nature Reviews Molecular Cell Biology,2007,8(7):519-529.
[32]Ozcan L,Ergin AS,Lu A,et al.Endoplasmic reticulum stress plays a central role in development of leptin resistance[J].Cell Metabolism,2009,9(1):35-51.
[33]Zhang X,Zhang G,Zhang H,et al.Hypothalamic IKKβ/NF-κBand ER stress link overnutrition to energy imbalance and obesity[J].Cell,2008,135(1):61-73.
[34]Murakami T,Iida M,Shima K.Dexamethasone regulates obese expression in isolated rat adipocytes[J].Biochemical and Biophysical Research Communications,1995,214(3):1260-1267.
[35]Kimura M,Tateishi N,Shiota T,et al.Long-term exercise downregulates leptin receptor mRNA in the arcuate nucleus[J].Neuroreport,2004,15(4):713-716.
[36]Tan Y,Chen WH,Guo L.Mechanism of exercise and diet interventions on central posterior rreceptor signaling of leptin resistance rats[J].China Sport Science,2011,31:57-66.
[37]Bj?rnholm M,Münzberg H,Leshan RL,et al.Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function[J].Journal of Clinical Investigation,2007,117(5):1354-1360.
[38]Bai X,Liu Z,Wang Y,et al.Down-regulation of suppressor of cytokines signaling 3 expression in hypothalamus attenuates highfat diet-induced obesity in rats[J].Chin J End Met,2012,28:63-67.
[39]Elchebly M,Payette P,Michaliszyn E,et al.Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene[J].Science,1999,283(5407):1544-1548.
[40]Bhattarai BR,Kafle B,Hwang JS,et al.Novel thiazolidinedione derivatives with anti-obesity effects:dual action as PTP1Binhibitors and PPAR-γactivators[J].Bioorganic and Medicinal Chemistry Letters,2010,20(22):6758-6763.
[41]Yu Y,Wu Y,Szabo A,et al.Teasaponin reduces inflammation and central leptin resistance in diet-induced obese male mice[J].Endocrinology,2013,154(9):3130-3140.
[42]Aubert G,Mansuy V,Voirol MJ,et al.The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression[J].Metabolism Clinical and Experimental,2011,60(3):327-334.
[43]Tam J,Cinar R,Liu J,et al.Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance[J].Cell Metabolism,2012,16(2):167-179.
[44]Mattace RG,Santoro A,Russo R,et al.Palmitoylethanolamide prevents metabolic alterations and restores leptin sensitivity in ovariectomized rats[J].Endocrinology,2014,155(4):1291-1301.
[45]Banks WA,Dipalma CR,Farrell CL.Impaired transport of leptin across the blood-brain barrier in obesity[J].Peptides,1999,20(11):1341-1345.
[46]Hsuchou H,Mishra PK,Kastin AJ,et al.Saturable leptin transport across the BBB persists in EAE mice[J].Journal of Molecular Neuroscience Mn,2013,51(2):364-370.
[47]Dietrich MO,Spuch C,Antequera D,et al.Megalin mediates the transport of leptin across the blood-CSF barrier[J].Neurobiology of Aging,2008,29(6):902-912.
[48]Yi X,Yuan D,Farr SA,et al.Pluronic modified leptin with increased systemic circulation,brain uptake and efficacy for treatment of obesity[J].Journal of Controlled Release,2014,191(15):34-46.
[49]Elinav E,Nivspector L,Katz M,et al.Pegylated leptin antagonist is a potent orexigenic agent:preparation and mechanism of activity[J].Endocrinology,2009,150(7):3083-3091.
[50]Hukshorn CJ,van Dielen FM,Buurman WA,et al.The effect of pegylated recombinant human leptin(PEG-OB)on weight loss and inflammatory status in obese subjects[J].International Journal of Obesity and Related Metabolic Disorders Journal of the International Association for the Study of Obesity,2002,26(4):504-509.
[51]Hosoi T,Miyahara T,Kayano T,et al.Fluvoxamine attenuated endoplasmic reticulum stress-induced leptin resistance[J].Frontiers in Endocrinology,2012,3:12.
[52]Hosoi T,Yamaguchi R,Noji K,et al.Flurbiprofen ameliorated obesity by attenuating leptin resistance induced by endoplasmic reticulum stress[J].Embo Molecular Medicine,2014,6(3):335-346.