Guo Kaiying, McMinn Julie E, Ludwig Thomas, Yu Yi-Hao, Yang Guoqing, Chen Lulu, Loh Daniella, Li Cai, Chua Streamson, Zhang Yiying
Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Endocrinology. 2007 Aug;148(8):3987-97. doi: 10.1210/en.2007-0261. Epub 2007 May 10.
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).
尽管中枢瘦素信号似乎在食物摄入和能量代谢的调节中起主要作用，但外周瘦素信号的生理作用及其对全身能量代谢的相对贡献仍不清楚。为了解决这个问题，我们使用他莫昔芬（Tam）诱导的Cre-LoxP系统创建了一种小鼠模型（Cre-Tam小鼠），该模型在大脑中具有完整的瘦素受体，但在肝脏、脂肪组织和小肠中瘦素受体的信号结构域几乎完全缺失。Cre-Tam小鼠出现明显的高瘦素血症（约4倍；P<0.01），同时瘦素的转录后产生增加了2.3倍（P<0.05）。虽然这与脂肪组织中瘦素产生的负反馈调节破坏一致，但能量平衡、体温调节和胰岛素敏感性没有明显变化。尽管存在高瘦素血症，但下丘脑磷酸化信号转导和转录激活因子3的水平、神经肽表达和食物摄入量均未改变。Cre-Tam小鼠血浆结合瘦素的百分比显著增加（90.1-96对41.8-74.7%；P<0.05），但血浆游离瘦素浓度保持不变。我们从这些结果得出结论：1）外周瘦素信号对全身能量代谢的相对贡献在体内微不足道；2）脂肪细胞中的瘦素信号构成了瘦素产生的一种独特的短环负反馈调节，与组织代谢状态无关；3）单独扰动外周瘦素信号，尽管会增加瘦素的产生，但由于瘦素结合蛋白水平的反调节增加，可能不足以改变瘦素的有效血浆水平。
