The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here, we show that, despite obesity, mice with reduced neuronal LPL (NEXCreLPL^flox (LPL KD)) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to wilt type (WT) controls (LPL^flox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence lifetime imaging microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of free vs. bound nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in or over-expressing LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver-related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism.

中文翻译：

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神经元脂蛋白脂肪酶缺乏症改变神经元功能和肝代谢。

肝脏代谢的自主调节为非酒精性脂肪肝疾病（NAFLD）的治疗提供了一个新的目标。但是，尚不清楚调节脑肝轴的神经元的分子特征。由于缺乏神经元脂蛋白脂肪酶（LPL）的小鼠在神经元脂质感应和系统能量平衡中会产生干扰，因此我们认为LPL可能是参与调节肝代谢的自主神经元的组成部分。在这里，我们显示，尽管肥胖，但与衰老型（WT）对照（LPL ^flox）相比，神经元LPL（NEXCreLPL ^flox（LPL KD））减少的小鼠显示出改善的葡萄糖耐量和减少的肝脂质积聚。）。为了确定LPL缺乏对神经元生理的影响，使用经突触逆行示踪剂PRV-152在下丘脑室旁核（PVN）中鉴定了肝脏相关的神经元。膜片钳研究显示LPL KD小鼠肝脏相关神经元的抑制性突触后电流减少。荧光寿命成像显微镜（FLIM）用于可视化LPL耗尽的神经元的代谢变化。相对于结合，对游离的与结合的烟酰胺腺嘌呤二核苷酸（NADH）和黄素腺嘌呤二核苷酸（FAD）进行定量分析显示，在LPL耗尽的神经元中，葡萄糖利用率和TCA循环通量增加。来自下丘脑细胞系缺乏或过表达LPL的整体代谢组学概括了这些发现。我们的数据表明LPL是PVN中肝脏相关的自主神经元的新特征。此外，LPL的损失足以引起神经元底物利用率和功能的改变，这可能先于肝代谢的改变。