STAT3 signalling is required for leptin regulation of energy balance but not reproduction
STAT3 signalling is required for leptin regulation of energy balance but not reproduction
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DOI：
10.1038/nature01388
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发表时间：
2003-02-20
期刊：
影响因子：
64.8
通讯作者：
Myers, MG
中科院分区：
文献类型：
--
作者：
Bates, SH;Stearns, WH;Myers, MG
脂肪细胞分泌的瘦素通过激活瘦素受体长型(LRB)将身体的能量状态传递给大脑。LRB调节能量平衡和神经内分泌功能；db/db小鼠缺乏LRB会导致肥胖、生长受损、不孕和糖尿病(1-4)。LRB的Tyr 1138在瘦素作用过程中介导转录因子STAT3的激活(5-8)。为了研究STAT3信号在体内对瘦素作用的贡献，我们用编码LRB中Tyr 1138的等位基因替换了小鼠的Lepr(Lepr)基因，该等位基因编码的丝氨酸残基(Lepr(S1138))特异性地破坏了LRB-STAT3信号。在这里，我们发现，与db/db小鼠一样，LEPR(S1138)纯合子(S/S)也是肥胖症患者。然而，db/db小鼠不育、矮小且患有糖尿病，而S/S小鼠则能生育、身长且血糖较低。此外，神经肽Y在db/db小鼠中的表达在db/db小鼠中升高，而在S/S小鼠中没有表达，而下丘脑黑素皮质素系统在db/db和S/S小鼠中都受到抑制。因此，LRB-STAT3信号介导瘦素对黑素皮质素的产生和身体能量平衡的影响，而不同的LRB信号调节NPY和生育、生长和葡萄糖平衡的控制。
Secretion of leptin from adipocytes communicates body energy status to the brain by activating the leptin receptor long form (LRb). LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes(1-4). Tyr 1138 of LRb mediates activation of the transcription factor STAT3 during leptin action(5-8). To investigate the contribution of STAT3 signalling to leptin action in vivo, we replaced the gene encoding the leptin receptor (lepr) in mice with an allele coding for a replacement of Tyr 1138 in LRb with a serine residue (lepr(S1138)) that specifically disrupts the LRb-STAT3 signal. Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese. However, whereas db/db mice are infertile, short and diabetic, s/s mice are fertile, long and less hyperglycaemic. Furthermore, hypothalamic expression of neuropeptide Y (NPY) is elevated in db/db mice but not s/s mice, whereas the hypothalamic melanocortin system is suppressed in both db/db and s/s mice. LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis.