Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities

Kaiying Guo, Julie E. McMinn, Thomas Ludwig, Yi Hao Yu, Guoqing Yang, Lulu Chen, Daniella Loh, Cai Li, Streamson C. Chua, Jr., Yiying Zhang

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Abstract

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).

Original languageEnglish (US)
Pages (from-to)3987-3997
Number of pages11
JournalEndocrinology
Volume148
Issue number8
DOIs
StatePublished - Aug 2007

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Leptin
Tamoxifen
Leptin Receptors
Energy Metabolism
Adipose Tissue
Appetite Regulation
STAT3 Transcription Factor
Body Temperature Regulation
Neuropeptides
Adipocytes
Small Intestine
Insulin Resistance
Eating

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Guo, K., McMinn, J. E., Ludwig, T., Yu, Y. H., Yang, G., Chen, L., ... Zhang, Y. (2007). Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities. Endocrinology, 148(8), 3987-3997. https://doi.org/10.1210/en.2007-0261

Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities. / Guo, Kaiying; McMinn, Julie E.; Ludwig, Thomas; Yu, Yi Hao; Yang, Guoqing; Chen, Lulu; Loh, Daniella; Li, Cai; Chua, Jr., Streamson C.; Zhang, Yiying.

In: Endocrinology, Vol. 148, No. 8, 08.2007, p. 3987-3997.

Research output: Contribution to journalArticle

Guo, K, McMinn, JE, Ludwig, T, Yu, YH, Yang, G, Chen, L, Loh, D, Li, C, Chua, Jr., SC & Zhang, Y 2007, 'Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities', Endocrinology, vol. 148, no. 8, pp. 3987-3997. https://doi.org/10.1210/en.2007-0261
Guo, Kaiying ; McMinn, Julie E. ; Ludwig, Thomas ; Yu, Yi Hao ; Yang, Guoqing ; Chen, Lulu ; Loh, Daniella ; Li, Cai ; Chua, Jr., Streamson C. ; Zhang, Yiying. / Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities. In: Endocrinology. 2007 ; Vol. 148, No. 8. pp. 3987-3997.
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