Leptin signaling pathway

Leptin is a peptide hormone mainly synthesised and secreted from adipocytes. It is also expressed in other tissues including placenta, stomach and skeletal muscle. Leptin mediates its effects by binding to its receptor, leptin receptor (LEPR). LEPR belongs to gp130 family of cytokine receptor. LEPR is expressed in many tissues such as brain, adipose tissue, heart, placenta, lung and liver. Alternative splicing of LEPR results in six different isoforms, LEPRa, LEPRb, LEPRc, LEPRd, LEPRe and LEPRf. LEPRb is the longest isoform and possess signaling capacity. The role of other isoforms in leptin signaling is not clear. Leptin plays a major role in the regulation of energy homeostasis and regulate food intake and energy expenditure. Leptin is found to be transported to various regions of the brain across blood brain barrier. Impairment in leptin signaling across the blood brain barrier induces leptin resistance and thus obesity. Leptin is known to regulate reproduction, bone homeostasis and immune signaling. Leptin is also implicated in various physiological processers such as angiogenesis and hematopoiesis. LEPRb forms a homodimer and binds to leptin in 1:1 stoichiometry. This tetrameric receptor/ ligand complex appears to be essential for signaling. Leptin receptor lacks intrinsic kinase activity. It mediates multiple signaling pathways by binding to cytoplasmic kinases such as Janus Kinase 2 (JAK2). Activation of JAK2 by leptin promotes the tyrosine phosphorylation of LEPRb at Tyr-986, Try-1078 and Tyr-1141, thus activating LEPRb. Activation of leptin receptor with leptin activates signaling modules such as JAK/STAT, RAS/RAF/MAPK, IRS1/PI-3K, PLCγ and AMPK/ACC modules. Tyrosine phosphorylation of LEPRb induces binding of STATs to LEPRb. Binding of STATs to the phosphorylated residues of LEPR leads to the JAK2 mediated tyrosine phosphorylation and activation of STATs. Activated STATs translocate to the nucleus and induces expression of genes such as suppressor of cytokine signaling 3 (SOCS3) and TIMP metallopeptidase inhibitor 1 (TIMP1). SOCS3 mediates feedback inhibition of leptin pathway by binding to Tyr-986 residue of LEPR. Cytosolic PTP1B also negatively regulates leptin pathway by dephosphorylating JAK2 and STAT3. Binding of leptin to its receptor results in the phosphorylation of PTPN1. Phosphorylated PTPN11 provides a docking site for GRB2, resulting in the activation of ERK module through RAS-RAF-MEK signaling. Leptin induces the activation of PI-3K by promoting the interaction and formation of SH2B/JAK2/IRS complex. Activation PI-3K mediates the activation of activation of protein kinases such as protein kinase B (AKT1) and downstream signaling cascades such as mammalian target of rapamycin (MTOR), nitric oxide synthase 3 (NOS3) and phosphodiesterase 3A, cGMP-inhibited (PDE3A). Activated AKT also regulates glycogen synthase kinase 3 alpha/beta (GSK3A/B) proteins. IkappaB kinases (IKKs) are activated in response to AKT activation. Activated IKKs induce nuclear translocation of NF-kappaB. Leptin also regulates 5'-AMP-activated protein kinase (AMPK) signaling. AMPK function as energy sensor and is activated in response to rise in AMP to ATP ratio. Activated AMPK regulate fatty acid biosymthesis by regulating the activity the enzyme, fatty acid biosynthesis-acetyl-CoA carboxylase (ACC). PLC gamma is activated in response to leptin signaling. Activated PLC gamma regulate intracellular calcium levels and also protein kinase C activation by hydrolysing phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Please access this pathway at [http://www.netpath.org/netslim/Leptin_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Nanjappa, V., Raju, R., Muthusamy, B., Sharma, J., Thomas, J. K., Nidhina, P. A. H., Harsha, H. C., Pandey, A., Anilkumar G. and Prasad, T. S. K. (2011). A comprehensive curated reaction map of leptin signaling pathway. Journal of Proteomics and Bioinformatics. 4, 184-189.

瘦素是一种主要在脂肪细胞中合成和分泌的肽类激素，亦在其他组织如胎盘、胃和骨骼肌中表达。瘦素通过与其受体——瘦素受体（LEPR）的结合来介导其效应。LEPR属于gp130家族的细胞因子受体。LEPR在包括大脑、脂肪组织、心脏、胎盘、肺和肝脏在内的许多组织中表达。LEPR的剪接变异导致产生六种不同的异构体，即LEPRa、LEPRb、LEPRc、LEPRd、LEPre和LEPRf。LEPRb是其中最长的异构体，并具有信号传导能力。其他异构体在瘦素信号传导中的作用尚不明确。瘦素在调节能量稳态、调节食物摄入和能量消耗方面发挥着重要作用。研究发现，瘦素能够穿越血脑屏障，运输到大脑的各个区域。血脑屏障上瘦素信号的损害会导致瘦素抵抗性增加，从而引发肥胖。瘦素还已知参与调节生殖、骨骼稳态和免疫信号传导。此外，瘦素还与多种生理过程有关，例如血管生成和造血。LEPRb形成同源二聚体，并以1:1的化学计量比与瘦素结合。这种四聚体受体/配体复合物对于信号传导似乎是必不可少的。瘦素受体缺乏内在的激酶活性，它通过结合细胞质激酶如Janus激酶2（JAK2）来介导多个信号通路。瘦素通过激活JAK2，促进LEPRb在Tyr-986、Try-1078和Tyr-1141位点的酪氨酸磷酸化，从而激活LEPRb。瘦素受体与瘦素结合激活的信号模块包括JAK/STAT、RAS/RAF/MAPK、IRS1/PI-3K、PLCγ和AMPK/ACC模块。LEPRb的酪氨酸磷酸化诱导STATs与LEPRb的结合。STATs与磷酸化的LEPR残基结合导致JAK2介导的酪氨酸磷酸化和STATs的激活。激活的STATs转移至细胞核，诱导表达如抑制细胞因子信号3（SOCS3）和TIMP金属蛋白酶抑制剂1（TIMP1）等基因。SOCS3通过结合LEPR的Tyr-986残基来介导瘦素途径的反馈抑制。细胞质中的PTP1B也通过去磷酸化JAK2和STAT3来负向调节瘦素途径。瘦素与其受体的结合导致PTPN1的磷酸化。磷酸化的PTPN11提供了GRB2的停靠位点，从而通过RAS-RAF-MEK信号传导激活ERK模块。瘦素通过促进SH2B/JAK2/IRS复合物的相互作用和形成来诱导PI-3K的激活。激活的PI-3K介导蛋白激酶如蛋白激酶B（AKT1）和下游信号级联如哺乳动物雷帕霉素靶蛋白（mTOR）、一氧化氮合酶3（NOS3）和磷酸二酯酶3A，cGMP抑制型（PDE3A）的激活。激活的AKT还调节糖原合成酶激酶3α/β（GSK3A/B）蛋白。在AKT激活的响应下，IkappaB激酶（IKKs）被激活。激活的IKKs诱导NF-kappaB的核转位。瘦素还调节5'-AMP激活的蛋白激酶（AMPK）信号传导。AMPK作为能量传感器，在AMP到ATP比例升高时被激活。激活的AMPK通过调节脂肪酸生物合成酶（ACC）的活性来调节脂肪酸生物合成。PLCγ在瘦素信号传导的响应下被激活。激活的PLCγ通过水解磷脂磷脂酰肌醇-4,5-二磷酸（PIP2）生成肌醇1,4,5-三磷酸（IP3）和二酰甘油（DAG）来调节细胞内钙水平和蛋白激酶C的激活。请访问[http://www.netpath.org/netslim/Leptin_pathway.html NetSlim]数据库获取此途径信息。若使用此途径，请引用以下论文：Nanjappa, V.，Raju, R.，Muthusamy, B.，Sharma, J.，Thomas, J. K.，Nidhina, P. A. H.，Harsha, H. C.，Pandey, A.，Anilkumar G. 和 Prasad, T. S. K. (2011). 瘦素信号传导途径的全面编辑反应图。蛋白质组学与生物信息学杂志。4，184-189。