Disruption of Peripheral Leptin Signaling in Mice Results in Hyperleptinemia without Associated Metabolic Abnormalities (original) (raw)

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1Division of Molecular Genetics (K.G., J.E.M., L.C., D.L., S.C., Y.Z.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

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1Division of Molecular Genetics (K.G., J.E.M., L.C., D.L., S.C., Y.Z.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

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3Departments of Cell Biology and Anatomy (T.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

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4Medicine (Y.-H.Y.), Columbia University, College of Physicians and Surgeons, New York, New York 10032

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5Department of Physiology (G.Y., C.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

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1Division of Molecular Genetics (K.G., J.E.M., L.C., D.L., S.C., Y.Z.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

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1Division of Molecular Genetics (K.G., J.E.M., L.C., D.L., S.C., Y.Z.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

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5Department of Physiology (G.Y., C.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

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1Division of Molecular Genetics (K.G., J.E.M., L.C., D.L., S.C., Y.Z.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

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1Division of Molecular Genetics (K.G., J.E.M., L.C., D.L., S.C., Y.Z.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

2Department of Pediatrics, Naomi Berrie Diabetes Center (Y.Z.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390

*Address all correspondence and requests for reprints to: Yiying Zhang, Ph.D., Division of Molecular Genetics, Columbia University, Russ Berrie Pavilion, 1150 St. Nicholas Avenue, New York, New York 10032.

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Received:

26 February 2007

Published:

01 August 2007

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Kaiying Guo, Julie E. McMinn, Thomas Ludwig, Yi-Hao Yu, Guoqing Yang, Lulu Chen, Daniella Loh, Cai Li, Streamson Chua, Yiying Zhang, Disruption of Peripheral Leptin Signaling in Mice Results in Hyperleptinemia without Associated Metabolic Abnormalities, Endocrinology, Volume 148, Issue 8, 1 August 2007, Pages 3987–3997, https://doi.org/10.1210/en.2007-0261
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Although central leptin signaling appears to play a major role in the regulation of food intake and energy metabolism, the physiological role of peripheral leptin signaling and its relative contribution to whole-body energy metabolism remain unclear. To address this question, we created a mouse model (Cre-Tam mice) with an intact leptin receptor in the brain but a near-complete deletion of the signaling domain of leptin receptor in liver, adipose tissue, and small intestine using a tamoxifen (Tam)-inducible Cre-LoxP system. Cre-Tam mice developed marked hyperleptinemia (∼4-fold; P < 0.01) associated with 2.3-fold increase (P < 0.05) in posttranscriptional production of leptin. Whereas this is consistent with the disruption of a negative feedback regulation of leptin production in adipose tissue, there were no discernable changes in energy balance, thermoregulation, and insulin sensitivity. Hypothalamic levels of phosphorylated signal transducer and activator of transcription 3, neuropeptide expression, and food intake were not changed despite hyperleptinemia. The percentage of plasma-bound leptin was markedly increased (90.1–96 vs. 41.8–74.7%; P < 0.05), but plasma-free leptin concentrations remained unaltered in Cre-Tam mice. We conclude from these results that 1) the relative contribution to whole-body energy metabolism from peripheral leptin signaling is insignificant in vivo, 2) leptin signaling in adipocyte constitutes a distinct short-loop negative feedback regulation of leptin production that is independent of tissue metabolic status, and 3) perturbation of peripheral leptin signaling alone, although increasing leptin production, may not be sufficient to alter the effective plasma levels of leptin because of the counter-regulatory increase in the level of leptin binding protein(s).

Copyright © 2007 by The Endocrine Society

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