Leptin is critical for energy balance, glucose homeostasis, and for metabolic and neuroendocrine adaptations to starvation. A prevalent model predicts that leptin’s actions are mediated through pro-opiomelanocortin (POMC) neurons that express leptin receptors (LEPRs). However, previous studies have used prenatal genetic manipulations, which may be subject to developmental compensation. Here, we tested the direct contribution of POMC neurons expressing LEPRs in regulating energy balance, glucose homeostasis and leptin secretion during fasting using a spatiotemporally controlled Lepr expression mouse model. We report a dissociation between leptin’s effects on glucose homeostasis versus energy balance in POMC neurons. We show that these neurons are dispensable for regulating food intake, but are required for coordinating hepatic glucose production and for the fasting-induced fall in leptin levels, independent of changes in fat mass. We also identify a role for sympathetic nervous system regulation of the inhibitory adrenergic receptor (ADRA2A) in regulating leptin production. Collectively, our findings highlight a previously unrecognized role of POMC neurons in regulating leptin levels.

中文翻译：

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表达瘦素受体的 POMC 神经元通过抑制瘦素水平来协调对禁食的代谢反应

瘦素对于能量平衡、葡萄糖稳态以及代谢和神经内分泌适应饥饿至关重要。一个流行的模型预测瘦素的作用是通过表达瘦素受体 (LEPR) 的阿黑皮素原 (POMC) 神经元介导的。然而，以前的研究使用了产前基因操作，这可能会受到发育补偿。在这里，我们使用时空控制的 Lepr 表达小鼠模型测试了表达 LEPR 的 POMC 神经元在禁食期间调节能量平衡、葡萄糖稳态和瘦素分泌方面的直接贡献。我们报告了瘦素对 POMC 神经元中葡萄糖稳态与能量平衡的影响之间的分离。我们表明这些神经元对于调节食物摄入是可有可无的，但对于协调肝脏葡萄糖的产生和禁食诱导的瘦素水平下降是必需的，与脂肪量的变化无关。我们还确定了抑制性肾上腺素能受体 (ADRA2A) 的交感神经系统调节在调节瘦素产生中的作用。总的来说，我们的研究结果突出了 POMC 神经元在调节瘦素水平方面以前未被认识到的作用。