Intracellular signalling pathways activated by leptin.
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Journal: 2006/March - Biochemical Journal
ISSN: 1470-8728
Abstract:
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.
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Biochem J 393(Pt 1): 7-20
PMID: 16336196

Intracellular signalling pathways activated by leptin

Department of Endocrinology, Clínica Universitaria de Navarra and Metabolic Research Laboratory, University of Navarra, 36 Avda. Pío XII, 31008 Pamplona, Spain
email se.vanu@kcebhurfg
Received 2005 Sep 26; Revised 2005 Oct 7; Accepted 2005 Oct 7.
Copyright The Biochemical Society, London

Abstract

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.

Keywords: adipocyte, cytokine, Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT pathway), leptin receptor, obesity, signalling cascade
Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, 5′-AMP-activated protein kinase; CNTF, ciliary neurotrophic factor; CT-1, cardiotrophin-1; ERK, extracellular-signal-regulated kinase; HIF-1α, hypoxia-inducible factor 1α; IL, interleukin; IRS, insulin receptor substrate; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LIF, leukaemia inhibitory factor; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; NPY, neuropeptide Y; OSM, oncostatin-M; PDE, phosphodiesterase; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PKC, protein kinase C; PTP1B, protein tyrosine phosphatase 1B; SH2, Src-like homology 2; SHP-2, SH2 domain-containing protein tyrosine phosphatase; SOCS, suppressor of cytokine signalling; STAT, signal transducer and activator of transcription; TNFα, tumour necrosis factor α; TYK2, tyrosine kinase 2; VEGF, vascular endothelial growth factor
Abstract

Acknowledgments

This work was supported by a grant from the Spanish Ministerio de Ciencia y Tecnología from the Plan Nacional de I+D+I (SAF2003-09225). The PIUNA (Plan Investigación Universidad de Navarra) Foundation is also gratefully acknowledged.

Acknowledgments

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