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Modulation of Direct Leptin Signaling by Soluble Leptin Receptor

Departments of Physiology (G.Y., H.G., A.B., X.Y., C.L.) and Internal Medicine (C.L.), Touchstone Center for Diabetes Research, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854

Address all correspondence and requests for reprints to: Cai Li, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8854. E-mail: Cai.Li{at}UTSouthwestern.edu.

Soluble leptin receptor (SLR) represents the major leptin binding activity in plasma. It is generated by alternative splicing of OB-R mRNA (OB-Re) and/or ectodomain shedding of membrane-spanning receptors. To determine the role of SLR in leptin activation of its long-form receptor, OB-Rb, we established in vitro assays using a cell line stably expressing OB-Rb. Human embryonic kidney 293 cell lines stably overexpressing OB-Rb show a dose-dependent leptin-induced signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation and STAT3-responsive luciferase (STAT3-luc) activity. We demonstrate that when SLR is incubated with free leptin, binding of leptin to OB-Rb is reduced, with corresponding decrease of leptin-induced STAT3 tyrosine phosphorylation and STAT3-luc activity. However, by preparing leptin/SLR mixtures containing the same amount of free leptin but increasing amounts of leptin-SLR complex, we show that leptin-SLR complex does not inhibit OB-Rb activation by free leptin. These results suggest that in settings in which leptin and SLR coexist, SLR may sequester leptin from productive interactions with OB-Rb. Because plasma SLR levels are independently regulated by many different physiological and pathophysiological conditions, SLR may modulate the actions of leptin in tissues in which direct action of leptin has been demonstrated.

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