Leptin receptor signaling and the regulation of mammalian physiology - PubMed (original) (raw)

Review

Leptin receptor signaling and the regulation of mammalian physiology

E C Villanueva et al. Int J Obes (Lond). 2008 Dec.

Abstract

The adipocyte-derived hormone, leptin, signals the status of body energy stores to the central nervous system to regulate appetite and energy expenditure. A specific long-form leptin receptor (LepRb), a type I cytokine receptor, mediates leptin action on LepRb-expressing neurons in the brain. Leptin binding to LepRb activates the associated Janus kinase-2 (Jak2) tyrosine kinase to promote the phosphorylation of Jak2 and three residues on LepRb; each of these sites mediates a distinct aspect of downstream LepRb signaling, with differing physiologic functions. Tyr(1138) --> STAT3 signaling suppresses feeding, but is not required for a number of other leptin actions. Tyr(985) binds SH2-containing tyrosine phosphatase-2 and suppressor of cytokine signaling-3 and primarily mediates the attenuation of LepRb signaling in vivo. The role for Tyr(1077), the major regulator of signal transducer and activator of transcription-5 (STAT5) during leptin signaling, in the physiologic response to leptin remains unclear, although the obese phenotype of animals deleted for STAT5 in the brain suggests the potential importance of this signaling pathway. Leptin also modulates a number of other signaling pathways in the brain, including PI 3-kinase, mammalian target of rapamycin and AMP-dependent protein kinase; the pathways by which leptin controls these signals remain unclear, however, and may involve some indirect mechanisms. Important issues regarding leptin action and LepRb signaling in the future include not only the more thorough analysis of intracellular signaling pathways, but the neural substrate by which leptin acts, as most major populations of LepRb neurons remain poorly studied.

PubMed Disclaimer

Figures

Figure 1

Mechanisms of LepRb signaling. Leptin binding to LepRb activates the Jak2 tyrosine kinase to initiate tyrosine-phosphorylation-dependent signal transduction pathways. In cultured cells, Tyr985 activates the SHP2/ERK cascade which activates RSK and the ribosomal protein S6 to promote translation (and which may modulate neuronal plasticity). Tyr985 also serves as a binding site for SOCS3 to inhibit LepRb signaling. Activation of Tyr1077 and Tyr1138 induces phosphorylation of STAT5 and STAT3, respectively (although Tyr1138 may also mediate a minor component of STAT5 phosphorylation), stimulating the translocation of STAT3 and STAT5 to the nucleus. While the pertinent transcriptional targets of STAT5 remain unknown, several STAT3 transcriptional targets have been identified, including SOCS3. We do not yet fully understand the mechanisms by which LepRb activates other signals, such as PI3K and mTORC1, in the hypothalamus.

References

1. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA. 2006;295:1549–1555. - PubMed
1. Tierney EF, Gregg EW, Narayan KM. Leading causes of death in the United States. JAMA. 2006;295:383. - PubMed
1. Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003;290:1884–1890. - PubMed
1. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395:763–770. - PubMed
1. Elmquist JK, Coppari R, Balthasar N, et al. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol. 2005;493:63–71. - PubMed

Leptin receptor signaling and the regulation of mammalian physiology - PubMed (original) (raw)