Hypothalamic Sirt1 regulates food intake in a rodent model system.
Hypothalamic Sirt1 regulates food intake in a rodent model system.
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DOI：
10.1371/journal.pone.0008322
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发表时间：
2009-12-15
期刊：
影响因子：
3.7
通讯作者：
Nillni EA
中科院分区：
文献类型：
--
作者：
Cakir I;Perello M;Lansari O;Messier NJ;Vaslet CA;Nillni EA
Sirt1是一种进化上保守的NAD+依赖性脱乙酰酶，参与广泛的过程，包括细胞分化、凋亡以及代谢和衰老。在这项研究中，我们研究了下丘脑Sirt1在能量平衡中的作用。下丘脑Sirt 1的药理学抑制或siRNA介导的敲低显示出减少食物摄入和体重增加。中枢给予特定的黑皮质素拮抗剂SHU9119，逆转了下丘脑Sirt1抑制的厌食作用，表明Sirt1通过中枢黑皮质素信号调节食物摄入。我们还表明，禁食增加下丘脑Sirt 1表达并减少FoxO 1（Forkhead转录因子）乙酰化，这表明Sirt 1以FoxO 1依赖性方式调节中枢黑皮质素系统。此外，下丘脑Sirt1显示出调节S6K信号传导，使得禁食诱导的Sirt1活性的抑制导致S6K通路的上调。因此，这是第一个提供下丘脑Sirt1在调节食物摄入和体重中的新作用的研究。考虑到Sirt1在几种外周组织和下丘脑中的作用，以Sirt1调节为中心的潜在疗法可能在治疗包括肥胖在内的代谢性疾病方面提供有前景的疗法。
Sirt1 is an evolutionarily conserved NAD+ dependent deacetylase involved in a wide range of processes including cellular differentiation, apoptosis, as well as metabolism, and aging. In this study, we investigated the role of hypothalamic Sirt1 in energy balance. Pharmacological inhibition or siRNA mediated knock down of hypothalamic Sirt1 showed to decrease food intake and body weight gain. Central administration of a specific melanocortin antagonist, SHU9119, reversed the anorectic effect of hypothalamic Sirt1 inhibition, suggesting that Sirt1 regulates food intake through the central melanocortin signaling. We also showed that fasting increases hypothalamic Sirt1 expression and decreases FoxO1 (Forkhead transcription factor) acetylation suggesting that Sirt1 regulates the central melanocortin system in a FoxO1 dependent manner. In addition, hypothalamic Sirt1 showed to regulate S6K signaling such that inhibition of the fasting induced Sirt1 activity results in up-regulation of the S6K pathway. Thus, this is the first study providing a novel role for the hypothalamic Sirt1 in the regulation of food intake and body weight. Given the role of Sirt1 in several peripheral tissues and hypothalamus, potential therapies centered on Sirt1 regulation might provide promising therapies in the treatment of metabolic diseases including obesity.
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