Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function
Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function
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DOI：
10.1172/jci30688
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发表时间：
2007-05-01
影响因子：
15.9
通讯作者：
Myers, Martin G., Jr.
中科院分区：
文献类型：
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作者：
Bjornholm, Marie;Munzberg, Heike;Myers, Martin G., Jr.
脂肪来源的激素，瘦素，通过其受体（LRb）将身体能量储存状态传递给大脑，减少摄食和增强神经内分泌能量消耗。大多数肥胖者体内的高水平瘦素无法促进体重减轻，这定义了一种对增加的瘦素反应减弱的状态，称为瘦素抵抗。瘦素刺激LRb上几个酪氨酸残基的磷酸化来介导瘦素的作用。我们同源地用在这些位点之一（Tyr985）发生突变的受体替换小鼠中的LRb，以检验其在瘦素作用和体内信号衰减中的作用。这种突变纯合的小鼠在神经内分泌学上是正常的，但雌性小鼠表现出摄食减少，产氧神经肽表达减少，免受高脂肪饮食引起的肥胖的影响，并且以性别偏倚的方式增加瘦素敏感性。因此，瘦素通过LRb Tyr985激活自身抑制信号，以减弱瘦素对肥胖的影响，特别是在女性中，可能导致肥胖的瘦素不敏感。
The adipose-derived hormone, leptin, acts via its receptor (LRb) to convey the status of body energy stores to the brain, decreasing feeding and potentiating neuroendocrine energy expenditure. The failure of high levels of leptin in most obese individuals to promote weight loss defines a state of diminished responsiveness to increased leptin, termed leptin resistance. Leptin stimulates the phosphorylation of several tyrosine residues on LRb to mediate leptin action. We homologously replaced LRb in mice with a receptor with a mutation in one of these sites (Tyr985) in order to examine its role in leptin action and signal attenuation in vivo. Mice homozygous for this mutation are neuroendocrinologically normal, but females demonstrate decreased feeding, decreased expression of orexigenic neuropeptides, protection from high-fat diet-induced obesity, and increased leptin sensitivity in a sex-biased manner. Thus, leptin activates autoinhibitory signals via LRb Tyr985 to attenuate the and-adiposity effects of leptin, especially in females, potentially contributing to leptin insensitivity in obesity.