Kublaoui Bassil M, Holder J Lloyd, Gemelli Terry, Zinn Andrew R
Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8591, USA.
Mol Endocrinol. 2006 Oct;20(10):2483-92. doi: 10.1210/me.2005-0483. Epub 2006 May 25.
Single-minded 1 (SIM1) is one of only six genes implicated in human monogenic obesity. Haploinsufficiency of this hypothalamic transcription factor is associated with hyperphagic obesity and increased linear growth in both humans and mice. Additionally, Sim1 heterozygous mice show enhanced hyperphagia and obesity in response to a high-fat diet. Thus the phenotype of Sim1 haploinsufficiency is similar to that of agouti yellow (Ay), and melanocortin 4 receptor (Mc4r) knockout mice, both of which are defective in hypothalamic melanocortin signaling. Sim1 and Mc4r are both expressed in the paraventricular nucleus (PVN). Here we report that Sim1 heterozygous mice, which have normal energy expenditure, are hyperphagic despite having elevated hypothalamic proopiomelanocortin (Pomc) expression. In response to the melanocortin agonist melanotan-2 (MTII) they exhibit a blunted suppression of feeding yet increase their energy expenditure normally. They also fail to activate PVN neurons in response to the drug at a dose that induces robust c-Fos expression in a subset of Sim1 PVN neurons in wild-type mice. The resistance to melanocortin signaling in Sim1 heterozygotes is not due to a reduced number of Sim1 neurons in the PVN. Hypothalamic Sim1 gene expression is induced by leptin and MTII treatment. Our results demonstrate that Sim1 heterozygotes are resistant to hypothalamic melanocortin signaling and suggest that Sim1-expressing PVN neurons regulate feeding, but not energy expenditure, in response to melanocortin signaling.
单 minded 1（SIM1）是仅有的六个与人类单基因肥胖相关的基因之一。这种下丘脑转录因子的单倍剂量不足与人类和小鼠的食欲亢进性肥胖以及线性生长增加有关。此外，Sim1 杂合子小鼠在高脂饮食下表现出更强的食欲亢进和肥胖。因此，Sim1 单倍剂量不足的表型与刺豚鼠黄色（Ay）和黑皮质素 4 受体（Mc4r）基因敲除小鼠相似，这两种小鼠在下丘脑黑皮质素信号传导方面均存在缺陷。Sim1 和 Mc4r 均在室旁核（PVN）中表达。在此我们报告，尽管下丘脑阿黑皮素原（Pomc）表达升高，但能量消耗正常的 Sim1 杂合子小鼠仍食欲亢进。对黑皮质素激动剂黑素otan - 2（MTII）的反应中，它们的摄食抑制作用减弱，但能量消耗正常增加。在能在野生型小鼠的一部分 Sim1 PVN 神经元中诱导强烈 c - Fos 表达的剂量下，它们对该药物也未能激活 PVN 神经元。Sim1 杂合子对黑皮质素信号传导的抵抗并非由于 PVN 中 Sim1 神经元数量减少。下丘脑 Sim1 基因表达可由瘦素和 MTII 处理诱导。我们的结果表明，Sim1 杂合子对下丘脑黑皮质素信号传导具有抗性，并提示表达 Sim1 的 PVN 神经元在对黑皮质素信号传导的反应中调节摄食，但不调节能量消耗。
