Leptin boosts cellular metabolism by activating AMPK and the sirtuins to reduce tau phosphorylation and β-amyloid in neurons.
Leptin boosts cellular metabolism by activating AMPK and the sirtuins to reduce tau phosphorylation and β-amyloid in neurons.
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DOI：
10.1016/j.bbrc.2011.09.050
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发表时间：
2011-10-14
影响因子：
3.1
通讯作者：
Tezapsidis, Nikolaos
中科院分区：
文献类型：
--
作者：
Greco, Steven J.;Hamzelou, Ashkan;Johnston, Jane M.;Smith, Mark A.;Ashford, J. Wesson;Tezapsidis, Nikolaos
瘦素是一种主要由脂肪细胞分泌的多效性激素。据报道，高密度的功能性瘦素受体在海马体和大脑的其他皮质区域表达，其生理意义尚未得到广泛探索。阿尔茨海默病 (AD) 的特点是大脑代谢受损，这些区域的葡萄糖利用率降低，而这些区域通常先于病理变化。最近的流行病学研究表明血浆瘦素可以预防 AD。具体来说，血浆瘦素水平处于最低四分位数的老年人患 AD 的可能性是最高四分位数的老年人的四倍。我们之前报道过瘦素通过涉及能量传感器、AMP 激活蛋白激酶 (AMPK) 的机制在体外调节 AD 病理通路。为此，我们研究了 AMPK 以及另一类将能量可用性与细胞代谢联系起来的传感器（SIRT）的激活在多大程度上介导瘦素的生物活性。瘦素直接激活细胞系中的神经元 AMPK 和 SIRT。此外，瘦素减少 tau 磷酸化和 β-淀粉样蛋白产生的能力分别对 AMPK 和 Sirtuin 抑制剂、化合物 C 和烟酰胺敏感。这些发现表明瘦素通常充当神经元能量稳态的信号。也许 AD 中的瘦素缺乏会导致处理能量需求时的神经元失衡，导致 Aβ 和磷酸 tau 蛋白升高，这可以通过补充低瘦素水平来恢复。这也可能是一种合理的治疗策略。
Leptin is a pleiotropic hormone primarily secreted by adipocytes. A high density of functional Leptin receptors has been reported to be expressed in the hippocampus and other cortical regions of the brain, the physiological significance of which has not been explored extensively. Alzheimer’s disease (AD) is marked by impaired brain metabolism with decreased glucose utilization in those regions which often precede pathological changes. Recent epidemiological studies suggest that plasma Leptin is protective against AD. Specifically, elderly with plasma Leptin levels in the lowest quartile were found to be four times more likely to develop AD than those in the highest quartile. We have previously reported that Leptin modulates AD pathological pathways in vitro through a mechanism involving the energy sensor, AMP-activated protein kinase (AMPK). To this end, we investigated the extent to which activation of AMPK as well as another class of sensors linking energy availability to cellular metabolism, the sirtuins (SIRT), mediate Leptin’s biological activity. Leptin directly activated neuronal AMPK and SIRT in cell lines. Additionally, the ability of Leptin to reduce tau phosphorylation and β-amyloid production was sensitive to the AMPK and sirtuin inhibitors, compound C and nicotinamide, respectively. These findings implicate that Leptin normally acts as a signal for energy homeostasis in neurons. Perhaps Leptin deficiency in AD contributes to a neuronal imbalance in handling energy requirements, leading to higher Aβ and phospho-tau, which can be restored by replenishing low Leptin levels. This may also be a legitimate strategy for therapy.
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DOI：
10.1093/geronj/42.1.78
发表时间：
1987-01-01
期刊：
JOURNALS OF GERONTOLOGY
影响因子：
--
作者：
INGRAM, DK;WEINDRUCH, R;WALFORD, RL
通讯作者：
WALFORD, RL
影响因子：
120.7
作者：
Lieb, Wolfgang;Beiser, Alexa S.;Vasan, Ramachandran S.;Tan, Zaldy S.;Au, Rhoda;Harris, Tamara B.;Roubenoff, Ronenn;Auerbach, Sanford;DeCarli, Charles;Wolf, Philip A.;Seshadri, Sudha
通讯作者：
Seshadri, Sudha
影响因子：
48
作者：
Bonda, David J.;Lee, Hyoung-gon;Camins, Antoni;Pallas, Merce;Casadesus, Gemma;Smith, Mark A.;Zhu, Xiongwei
通讯作者：
Zhu, Xiongwei
影响因子：
5.5
作者：
Morton, Gregory J.
通讯作者：
Morton, Gregory J.
影响因子：
11.8
作者：
Fulco, Marcella;Cen, Yana;Sartorelli, Vittorio
通讯作者：
Sartorelli, Vittorio