Deficiency of p62/Sequestosome 1 Causes Hyperphagia Due to Leptin Resistance in the Brain
Deficiency of p62/Sequestosome 1 Causes Hyperphagia Due to Leptin Resistance in the Brain
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DOI：
10.1523/jneurosci.2954-12.2013
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发表时间：
2013-09-11
影响因子：
5.3
通讯作者：
Sakurai, Takeshi
中科院分区：
文献类型：
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作者：
Harada, Harumi;Warabi, Eiji;Sakurai, Takeshi
已知胞质调节蛋白p62（Sequestosome 1/A170）调节多种受体介导的细胞内信号传导途径。p62缺陷被证明会导致小鼠成熟型肥胖，但这种异常的机制仍不清楚。在这里，我们报告，由于中枢瘦素抵抗引起的摄食过多是p62（-/-）小鼠肥胖的原因。我们发现这些小鼠表现出食欲过盛。将食物限制在野生型小鼠的进食量可以防止体重过度增加和脂肪积累，这表明过度喂养是p62（-/-）小鼠肥胖的主要原因。脑特异性p62缺陷导致成熟型肥胖的程度与p62（-/-）小鼠相同，进一步支持神经元机制是这些小鼠肥胖的主要原因。免疫组织化学分析显示，p62在下丘脑神经元中高度表达，包括弓状核的POMC神经元。甚至在年轻的肥胖前期p62（-/-）小鼠中也观察到中枢瘦素抵抗。我们在p62（-/-）小鼠中发现了转录因子Stat 3的细胞内分布缺陷，该转录因子Stat 3对瘦素的作用至关重要。这些结果表明，脑p62通过调节中枢瘦素信号通路在体重控制中起着重要作用，并且脑中缺乏p62会导致瘦素抵抗，从而导致摄食过多。因此，p62可能成为治疗肥胖和代谢综合征的临床靶点。
The cytoplasmic regulatory protein p62 (Sequestosome 1/A170) is known to modulate various receptor-mediated intracellular signaling pathways. p62 deficiency was shown to result in mature-onset obesity in mice, but the mechanisms underlying this abnormality remained unclear. Here we report that hyperphagia due to central leptin resistance is the cause of obesity in p62(-/-) mice. We found that these mice show hyperphagia. Restriction of food to the amount eaten by wild-type mice prevented excess body weight gain and fat accumulation, suggesting that overfeeding is the primary cause of obesity in p62(-/-) mice. Brain-specific p62 deficiency caused mature-onset obesity to the same extent as in p62(-/-) mice, further supporting a neuronal mechanism as the major cause of obesity in these mice. Immunohistochemical analysis revealed that p62 is highly expressed in hypothalamic neurons, including POMC neurons in the arcuate nucleus. Central leptin resistance was observed even in young preobese p62(-/-) mice. We found a defect in intracellular distribution of the transcription factor Stat3, which is essential for the action of leptin, in p62(-/-) mice. These results indicate that brain p62 plays an important role in bodyweight control by modulating the central leptin-signaling pathway and that lack of p62 in the brain causes leptin resistance, leading to hyperphagia. Thus, p62 could be a clinical target for treating obesity and metabolic syndrome.