Objective

Sirt6 is an essential regulator of energy metabolism in multiple peripheral tissues. However, the direct role of Sirt6 in the hypothalamus, specifically pro-opiomelanocortin (POMC) neurons, controlling energy balance has not been established. Here, we aimed to determine the role of Sirt6 in hypothalamic POMC neurons in the regulation of energy balance and the underlying mechanisms.

Methods

For overexpression studies, the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice was targeted bilaterally and adenovirus was delivered by using stereotaxic apparatus. For knockout studies, the POMC neuron-specific Sirt6 knockout mice (PKO mice) were generated. Mice were fed with chow diet or high-fat diet, and body weight and food intake were monitored. Whole-body energy expenditure was determined by metabolic cages. Parameters of body composition and glucose/lipid metabolism were evaluated.

Results

Sirt6 overexpression in the ARC ameliorated diet-induced obesity. Conversely, selective Sirt6 ablation in POMC neurons predisposed mice to obesity and metabolic disturbances. PKO mice showed an increased fat mass and food intake, while the energy expenditure was decreased. Mechanistically, Sirt6 could modulate leptin signaling in hypothalamic POMC neurons, with Sirt6 deficiency impairing leptin-induced phosphorylation of signal transducer and activator of transcription 3. The effects of leptin on reducing food intake and body weight and leptin-stimulated lipolysis were also impaired. Moreover, Sirt6 inhibition diminished the leptin-induced depolarization of POMC neurons.

Conclusions

Our results reveal a key role of Sirt6 in POMC neurons against energy imbalance, suggesting that Sirt6 is an important molecular regulator for POMC neurons to promote negative energy balance.

中文翻译：

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前视神经皮质素神经元中的Sirt6通过调节瘦素信号传导来控制能量代谢。

目的

Sirt6是多种周围组织能量代谢的重要调节剂。然而，Sirt6在下丘脑，特别是促视神经黑色素皮质激素（POMC）神经元中，控制能量平衡的直接作用尚未确定。在这里，我们旨在确定Sirt6在下丘脑POMC神经元在调节能量平衡和潜在机制中的作用。

方法

为了进行过表达研究，将饮食诱导的肥胖小鼠的下丘脑弓形核（ARC）进行了双向靶向，并使用立体定位仪递送了腺病毒。为了进行基因敲除研究，生成了POMC神经元特异性Sirt6基因敲除小鼠（PKO小鼠）。用低脂饮食或高脂饮食喂养小鼠，并监测体重和食物摄入。全身能量消耗取决于代谢笼。评价了身体成分和葡萄糖/脂质代谢的参数。

结果

ARC中Sirt6的过度表达改善了饮食引起的肥胖。相反，在POMC神经元中选择性Sirt6消融使小鼠容易出现肥胖和代谢紊乱。PKO小鼠显示脂肪量和食物摄入增加，而能量消耗减少。从机制上讲，Sirt6可以调节下丘脑POMC神经元中的瘦素信号传导，而Sirt6缺乏会损害瘦素诱导的信号转导和转录激活因子3的磷酸化。瘦素对减少食物摄入和体重的影响以及瘦素刺激的脂解作用也受到损害。此外，Sirt6抑制作用可减少瘦素诱导的POMC神经元去极化。

结论

我们的结果揭示了Sirt6在POMC神经元中对抗能量失衡的关键作用，这表明Sirt6是POMC神经元中促进负能量平衡的重要分子调节剂。