Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons
Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons
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DOI：
10.1016/j.cmet.2007.02.004
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发表时间：
2007-03-01
期刊：
影响因子：
29
通讯作者：
Cowley, Michael A.
中科院分区：
文献类型：
--
作者：
Enriori, Pablo J.;Evans, Anne E.;Cowley, Michael A.
尽管瘦素水平很高，但大多数肥胖的人类和啮齿动物对其食欲抑制作用缺乏反应。我们证明瘦素调节瘦小鼠ARH的NPY/AgRP和α-MSH分泌。高脂饮食诱导的肥胖（DIO）小鼠具有正常的ObRb水平和增加的SOCS-3水平，但瘦素不能调节肽分泌和瘦素信号级联的任何元件。尽管存在这种瘦素抗性，DIO小鼠中ARH下游的黑皮质素系统对黑皮质素激动剂过度反应，这可能是由于MC 4 R的上调。最后，我们表明，通过减少小鼠饮食中的脂肪含量，瘦素反应的NPY/AgRP和IPOMC神经元同时恢复，小鼠恢复正常的瘦素敏感性和血糖控制。这些结果突出了瘦素感应在黑皮质素回路中的生理重要性，并表明它们的瘦素感应的丧失可能导致瘦素抵抗的病理学。
Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and alpha-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and IPOMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.