Region-specific leptin resistance within the hypothalamus of diet-induced obese mice
Region-specific leptin resistance within the hypothalamus of diet-induced obese mice
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DOI：
10.1210/en.2004-0726
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发表时间：
2004-11-01
期刊：
影响因子：
4.8
通讯作者：
Bjorbæk, C
中科院分区：
文献类型：
--
作者：
Münzberg, H;Flier, JS;Bjorbæk, C
饮食诱导的肥胖（DIO）小鼠中的瘦素抵抗的特征在于血清瘦素升高和对外源性瘦素的反应降低，并且是由中枢神经系统中的未知缺陷引起的。瘦素通常作用于几个脑核团，但尚未报道个别脑区域内瘦素抵抗的详细描述。我们首先使用磷酸化信号转导子和转录激活子（P-STAT 3）免疫组织化学方法绘制了DIO小鼠脑中瘦素反应细胞的图谱。高脂饮食喂养16周后，弓状核（ARC）内瘦素激活的P-STAT 3染色显着减少。与此相反，其他下丘脑和下丘脑外核团仍然瘦素敏感。减少瘦素诱导的P-STAT 3在ARC中也可以检测到4周后，早在6天的高脂肪饮食。为了研究DIO小鼠ARC中瘦素抗性STAT 3激活的潜在机制，我们测量了瘦素受体-STAT 3通路中候选信号分子的mRNA水平。我们发现，细胞因子信号抑制因子3（SOCS-3），瘦素信号的抑制剂，在DIO小鼠的ARC中的水平特异性增加。该研究表明，ARC在DIO小鼠中选择性地抵抗瘦素，这可能是由下丘脑核中细胞因子信号传导抑制因子3的升高引起的。ARC中瘦素作用的缺陷可能在瘦素抵抗性肥胖的发病机制中起作用。
Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.