Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi-shi, Gunma, 371-8512, Japan,
Diabetologia. 2014 Apr;57(4):819-31. doi: 10.1007/s00125-013-3140-5. Epub 2013 Dec 29.
AIMS/HYPOTHESIS: Obesity is associated with ageing and increased energy intake, while restriction of energy intake improves health and longevity in multiple organisms; the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) is implicated in this process. Pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus are critical for energy balance regulation, and the level of SIRT1 protein decreases with age in the ARC. In the current study we tested whether conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevents age-associated weight gain and diet-induced obesity.
We targeted Sirt1 cDNA sequence into the Rosa26 locus and generated conditional Sirt1 knock-in mice. These mice were crossed with mice harbouring either Pomc-Cre or Agrp-Cre and the metabolic variables, food intake, energy expenditure and sympathetic activity in adipose tissue of the resultant mice were analysed. We also used a hypothalamic cell line to investigate the molecular mechanism by which Sirt1 overexpression modulates leptin signalling.
Conditional Sirt1 overexpression in mouse POMC or AgRP neurons prevented age-associated weight gain; overexpression in POMC neurons stimulated energy expenditure via increased sympathetic activity in adipose tissue, whereas overexpression in AgRP neurons suppressed food intake. SIRT1 improved leptin sensitivity in hypothalamic neurons in vitro and in vivo by downregulating protein-tyrosine phosphatase 1B, T cell protein-tyrosine phosphatase and suppressor of cytokine signalling 3. However, these phenotypes were absent in mice consuming a high-fat, high-sucrose diet due to decreases in ARC SIRT1 protein and hypothalamic NAD(+) levels.
CONCLUSIONS/INTERPRETATION: ARC SIRT1 is a negative regulator of energy balance, and decline in ARC SIRT1 function contributes to disruption of energy homeostasis by ageing and diet-induced obesity.
目的/假设：肥胖与衰老和能量摄入增加有关，而限制能量摄入可以改善多种生物的健康和寿命；烟酰胺腺嘌呤二核苷酸（NAD(+)-）依赖性去乙酰化酶 SIRT1（沉默调节蛋白 1）与这一过程有关。弓状核（ARC）中的前阿黑皮素原（POMC）和刺鼠相关肽（AgRP）神经元对于能量平衡调节至关重要，并且 ARC 中的 SIRT1 蛋白水平随着年龄的增长而降低。在目前的研究中，我们测试了在小鼠 POMC 或 AgRP 神经元中条件性过表达 Sirt1 是否可以预防与年龄相关的体重增加和饮食诱导的肥胖。
我们将 Sirt1 cDNA 序列靶向 Rosa26 基因座，并生成了条件性 Sirt1 敲入小鼠。这些小鼠与携带 Pomc-Cre 或 Agrp-Cre 的小鼠交配，分析了由此产生的小鼠的代谢变量、食物摄入、能量消耗和脂肪组织中的交感神经活动。我们还使用下丘脑细胞系研究了 Sirt1 过表达调节瘦素信号的分子机制。
在小鼠 POMC 或 AgRP 神经元中条件性过表达 Sirt1 可预防与年龄相关的体重增加；POMC 神经元中的过表达通过增加脂肪组织中的交感神经活动刺激能量消耗，而 AgRP 神经元中的过表达则抑制食物摄入。SIRT1 通过下调蛋白酪氨酸磷酸酶 1B、T 细胞蛋白酪氨酸磷酸酶和细胞因子信号转导抑制因子 3，在体外和体内改善了下丘脑神经元对瘦素的敏感性。然而，由于 ARC SIRT1 蛋白和下丘脑 NAD(+) 水平的降低，这些表型在食用高脂肪、高蔗糖饮食的小鼠中消失了。
结论/解释：ARC SIRT1 是能量平衡的负调节剂，ARC SIRT1 功能的下降导致衰老和饮食诱导肥胖破坏了能量稳态。
