title: Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities.
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 (approximately 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).
authors.affiliation: Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Kaiying
authors.initials: K
authors.lastname: Guo
authors.forename: Julie E
authors.initials: JE
authors.lastname: McMinn
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Yi-Hao
authors.initials: YH
authors.lastname: Yu
authors.forename: Guoqing
authors.initials: G
authors.lastname: Yang
authors.forename: Lulu
authors.initials: L
authors.lastname: Chen
authors.forename: Daniella
authors.initials: D
authors.lastname: Loh
authors.forename: Cai
authors.initials: C
authors.lastname: Li
authors.forename: Streamson
authors.initials: S
authors.lastname: Chua
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D004965:Estrogen Antagonists; D005091:Exons / Q000235:genetics; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D006706:Homeostasis / Q000502:physiology; D007333:Insulin Resistance; D019426:Integrases / Q000235:genetics; D007421:Intestine, Small / Q000378:metabolism; D020738:Leptin / Q000097:blood* / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017434:Protein Structure, Tertiary; D012326:RNA Splicing / Q000502:physiology; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D054411:Receptors, Leptin; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen
chemical_list: D004965:Estrogen Antagonists; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases