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, 393 (Pt 1), 7-20

Intracellular Signalling Pathways Activated by Leptin


Intracellular Signalling Pathways Activated by Leptin

Gema Frühbeck. Biochem J.


Leptin is a versatile 16 kDa peptide hormone, with a tertiary structure resembling that of members of the long-chain helical cytokine family. It is mainly produced by adipocytes in proportion to fat size stores, and was originally thought to act only as a satiety factor. However, the ubiquitous distribution of OB-R leptin receptors in almost all tissues underlies the pleiotropism of leptin. OB-Rs belong to the class I cytokine receptor family, which is known to act through JAKs (Janus kinases) and STATs (signal transducers and activators of transcription). The OB-R gene is alternatively spliced to produce at least five isoforms. The full-length isoform, OB-Rb, contains intracellular motifs required for activation of the JAK/STAT signal transduction pathway, and is considered to be the functional receptor. Considerable evidence for systemic effects of leptin on body mass control, reproduction, angiogenesis, immunity, wound healing, bone remodelling and cardiovascular function, as well as on specific metabolic pathways, indicates that leptin operates both directly and indirectly to orchestrate complex pathophysiological processes. Consistent with leptin's pleiotropic role, its participation in and crosstalk with some of the main signalling pathways, including those involving insulin receptor substrates, phosphoinositide 3-kinase, protein kinase B, protein kinase C, extracellular-signal-regulated kinase, mitogen-activated protein kinases, phosphodiesterase, phospholipase C and nitric oxide, has been observed. The impact of leptin on several equally relevant signalling pathways extends also to Rho family GTPases in relation to the actin cytoskeleton, production of reactive oxygen species, stimulation of prostaglandins, binding to diacylglycerol kinase and catecholamine secretion, among others.


Figure 1
Figure 1. Leptin receptor internalization
Schematic representation of lysosomal internalization and degradation of leptin receptors via clathrin-coated vesicles.
Figure 2
Figure 2. Role of phosphotyrosines of OB-Rb in leptin signalling
JAK2 associates with the receptor via the box1 motif. The long isoform leptin (L) receptor (OB-Rb) contains four important tyrosine residues (Tyr974, Tyr985, Tyr1077 and Tyr1138). These phosphorylated tyrosine residues provide docking sites for signalling proteins with SH2 domains. Most importantly, Tyr1138 recruits the transcription factor STAT3, which is subsequently phosphorylated by JAK2, dimerizes and translocates to the nucleus, where it induces SOCS3 and POMC (pro-opiomelanocortin) expression, while repressing AgRP (agouti-related peptide). SOCS proteins inhibit signalling by binding to phosphorylated JAK proteins or interacting directly with tyrosine-phosphorylated receptors. The ability of SOCS3 to inhibit leptin-stimulated phosphorylation of JAK2 and ERK provides a negative-feedback mechanism on the leptin signalling system. Grb-2, growth factor receptor binding-2.
Figure 3
Figure 3. Mechanisms of JAK/STAT activation through OB-Rb
Upon leptin (L) binding, a conformational change takes place (A) that allows juxtaposition of JAKs, which then become activated and are able to tyrosine-phosphorylate other JAKs and tyrosine residues on the receptor (B). Activation of JAK2 occurs by transphosphorylation and subsequent phosphorylation of tyrosine residues in the cytoplasmic region of the receptor. Phosphorylation of Tyr1138 allows association of STATs, which then become substrates of receptor-associated JAKs. Phosphorylation of STATs leads to their dissociation from the receptor and the formation of active dimers (C), which translocate to the nucleus to regulate gene expression, binding to the promoter regions of target genes (D).
Figure 4
Figure 4. Proposed model for the participation of SOCS3 in leptin resistance
During prolonged receptor stimulation by leptin (L), the inhibition of JAK2 and ERK phosphorylation is mediated by SOCS3 independently of Tyr985 of OB-Rb.
Figure 5
Figure 5. The MAPK pathway in leptin signalling
The ERK members of the MAPK family are components of the well-defined Ras/Raf/MAPK signalling cascade and have become activated by leptin (L). For more detailed information, see the text. DAG, diacylglycerol; Grb-2, growth factor receptor binding-2; PI3, PtdIns(3,4,5)P3; PLC, phospholipase C; SOS, son of sevenless.
Figure 6
Figure 6. The PI3K/PDE3B/cAMP cascade
Stimulation of the PI3K pathway by leptin (L) represents a key cascade to exert several different effects of the hormone at multiple sites. For more detailed information, see the text. C/EBP, CCAAT/enhancer-binding protein; eNOS, endothelial nitric oxide synthase; GSK3, glycogen synthase kinase 3.
Figure 7
Figure 7. Cross-talk of leptin signalling with insulin-induced pathways
Leptin (L) receptor (OB-Rb) activation acts through some of the components of the insulin signalling cascade, recruiting several IRSs. PIP2, PtdIns(4,5)P2, PIP3, PtdIns(3,4,5)P3.
Figure 8
Figure 8. Signalling pathways reported to be regulated by leptin
The schematic diagram summarizes the numerous and diverse pathways in which leptin has been shown to be involved. DGK, diacylglycerol kinase; PG, prostaglandin; PLC, phospholipase C; ROS, reactive oxygen species. Modified from Cellular Signalling, vol. 14, Sweeney, G., ‘Leptin signalling’, pp. 655–663, © 2002, with permission from Elsevier.

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