Leptin Deficiency and Diet-Induced Obesity Reduce Hypothalamic Kisspeptin Expression in Mice
Leptin Deficiency and Diet-Induced Obesity Reduce Hypothalamic Kisspeptin Expression in Mice
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DOI：
10.1210/en.2010-1100
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发表时间：
2011-04-01
期刊：
影响因子：
4.8
通讯作者：
Anderson, Greg M.
中科院分区：
文献类型：
--
作者：
Quennell, Janette H.;Howell, Christopher S.;Anderson, Greg M.
激素瘦素调节多种生物功能，包括能量稳态和生殖。瘦素通过对前脑神经元的间接作用促进GnRH功能。我们测试了瘦素缺乏或瘦素抵抗是否由于高脂饮食（HFD）可以调节有效的生殖神经肽kisspeptin。在雌二醇水平正常化的小鼠中，瘦素缺乏显著降低了kisspeptin基因的表达，特别是在弓状核（ARC），和kisspeptin免疫反应细胞在第三脑室（RP 3V）的头侧脑室周围区域的数量。HFD模型用于确定饮食诱导的肥胖和中枢瘦素抵抗对kisspeptin细胞数量和基因表达的影响。DBA/2 J小鼠，这是容易HFD诱导的不孕症，表现出显着减少Kisspeptin的表达在RP 3V和ARC和细胞数量在RP 3V HFD后。这是Kisspeptin可以通过HFD和/或体重增加来调节的第一个证据。接下来，我们证明了瘦素不直接在RP 3V中表达kisspeptin的神经元上发出信号（通过信号转导子和转录激活子3或5，或雷帕霉素的哺乳动物靶标）。最后，在瘦素受体缺陷小鼠中，在排卵前GnRH/LH峰诱导期间，GnRH和kisspeptin神经元均未被激活，表明瘦素对GnRH的作用可能在kisspeptin神经元的上游。这些数据提供的证据表明，瘦素对生殖功能的影响是由kisspeptin神经元在ARC和RP 3V，虽然在后者的网站的影响可能是间接的。（内分泌学152：1541-1550，2011）
The hormone leptin modulates a diverse range of biological functions, including energy homeostasis and reproduction. Leptin promotes GnRH function via an indirect action on forebrain neurons. We tested whether leptin deficiency or leptin resistance due to a high-fat diet (HFD) can regulate the potent reproductive neuropeptide kisspeptin. In mice with normalized levels of estradiol, leptin deficiency markedly reduced kisspeptin gene expression, particularly in the arcuate nucleus (ARC), and kisspeptin immunoreactive cell numbers in the rostral periventricular region of the third ventricle (RP3V). The HFD model was used to determine the effects of diet-induced obesity and central leptin resistance on kisspeptin cell number and gene expression. DBA/2J mice, which are prone to HFD-induced infertility, showed a marked decrease in kisspeptin expression in both the RP3V and ARC and cell numbers in the RP3V after HFD. This is the first evidence that kisspeptin can be regulated by HFD and/or increased body weight. Next we demonstrated that leptin does not signal (via signal transducer and activator of transcription 3 or 5, or mammalian target of rapamycin) directly on kisspeptin-expressing neurons in the RP3V. Lastly, in leptin receptor-deficient mice, neither GnRH nor kisspeptin neurons were activated during a preovulatory-like GnRH/LH surge induction regime, indicating that leptin's actions on GnRH may be upstream of kisspeptin neurons. These data provide evidence that leptin's effects on reproductive function are regulated by kisspeptin neurons in both the ARC and RP3V, although in the latter site the effects are likely to be indirect. (Endocrinology 152: 1541-1550, 2011)