Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice
Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice
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DOI：
10.1172/jci59816
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发表时间：
2012-03-01
影响因子：
15.9
通讯作者：
Elmquist, Joel K.
中科院分区：
文献类型：
--
作者：
Berglund, Eric D.;Vianna, Claudia R.;Elmquist, Joel K.
瘦素对其受体（LEPR）的作用刺激能量消耗，减少食物摄入，从而降低体重。一种介导这些对能量平衡影响的瘦素敏感靶细胞是阿黑皮素原（POMC）神经元。最近的证据表明，瘦素对POMC神经元的作用独立于其对能量平衡的影响来调节葡萄糖稳态。在这里，我们已经解剖了生理的影响，直接瘦素作用POMC神经元使用的小鼠模型，其中内源性LEPR的表达被阻止LoxP侧翼的转录阻断剂（loxTB），但可以重新激活Cre重组酶。Lepr（loxTB）等位基因纯合子小鼠肥胖，表现出LEPR缺陷的特征性缺陷。仅在下丘脑弓状核的POMC神经元中LEPR的重新表达并没有减少食物摄入，但部分正常化能量消耗并适度降低体重。尽管对能量平衡有中度影响，且与体重变化无关，但恢复POMC神经元中的LEPR使血糖正常化，并改善肝脏胰岛素抵抗、高胰高血糖素血症和血脂异常。总的来说，这些结果表明，对POMC神经元的直接瘦素作用不会减少食物摄入，但足以使缺乏LEPR的小鼠的葡萄糖和胰高血糖素水平正常化。
Leptin action on its receptor (LEPR) stimulates energy expenditure and reduces food intake, thereby lowering body weight. One leptin-sensitive target cell mediating these effects on energy balance is the proopiomelanocortin (POMC) neuron. Recent evidence suggests that the action of leptin on POMC neurons regulates glucose homeostasis independently of its effects on energy balance. Here, we have dissected the physiological impact of direct leptin action on POMC neurons using a mouse model in which endogenous LEPR expression was prevented by a LoxP-flanked transcription blocker (loxTB), but could be reactivated by Cre recombinase. Mice homozygous for the Lepr(loxTB) allele were obese and exhibited defects characteristic of LEPR deficiency. Reexpression of LEPR only in POMC neurons in the arcuate nucleus of the hypothalamus did not reduce food intake, but partially normalized energy expenditure and modestly reduced body weight. Despite the moderate effects on energy balance and independent of changes in body weight, restoring LEPR in POMC neurons normalized blood glucose and ameliorated hepatic insulin resistance, hyperglucagonemia, and dyslipidemia. Collectively, these results demonstrate that direct leptin action on POMC neurons does not reduce food intake, but is sufficient to normalize glucose and glucagon levels in mice otherwise lacking LEPR.