Hypothalamic SIRT1 prevents age-associated weight gain by improving leptin sensitivity in mice.
Hypothalamic SIRT1 prevents age-associated weight gain by improving leptin sensitivity in mice.
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DOI：
10.1007/s00125-013-3140-5
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发表时间：
2014-04
期刊：
影响因子：
8.2
通讯作者：
Kitamura, Tadahiro
中科院分区：
文献类型：
--
作者：
Sasaki, Tsutomu;Kikuchi, Osamu;Shimpuku, Mayumi;Susanti, Vina Yanti;Yokota-Hashimoto, Hiromi;Taguchi, Ryo;Shibusawa, Nobuyuki;Sato, Takashi;Tang, Lijun;Amano, Kosuke;Kitazumi, Tomoya;Kuroko, Mitsutaka;Fujita, Yuki;Maruyama, Jun;Lee, Yong-soo;Kobayashi, Masaki;Nakagawa, Takashi;Minokoshi, Yasuhiko;Harada, Akihiro;Yamada, Masanobu;Kitamura, Tadahiro
关键词：
肥胖与衰老和能量摄入增加有关，而限制能量摄入可改善多种生物体的健康和寿命; NAD+依赖性脱乙酰酶sirtuin 1（SIRT 1）与此过程有关。下丘脑弓状核（ARC）中的阿黑皮素原（POMC）和刺鼠相关肽（AgRP）神经元对能量平衡调节至关重要，并且ARC中SIRT 1蛋白水平随年龄而降低。在目前的研究中，我们测试了小鼠POMC或AgRP神经元中的条件性Sirt 1过表达是否可以预防年龄相关的体重增加和饮食诱导的肥胖。我们将Sirt 1 cDNA序列靶向Rosa 26位点，并产生条件性Sirt 1敲入小鼠。将这些小鼠与携带Pomc-Cre或Agrp-Cre的小鼠杂交，并分析所得小鼠脂肪组织中的代谢变量、食物摄入、能量消耗和交感神经活性。我们还使用下丘脑细胞系研究Sirt 1过表达调节瘦素信号传导的分子机制。小鼠POMC或AgRP神经元中的条件性Sirt 1过表达阻止了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性刺激能量消耗，而AgRP神经元中的过表达抑制了食物摄入。SIRT 1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，在体外和体内提高下丘脑神经元的瘦素敏感性。然而，由于ARC SIRT 1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不存在。ARC SIRT 1是能量平衡的负调节因子，ARC SIRT 1功能的下降导致衰老和饮食诱导的肥胖破坏能量稳态。本文的在线版本（doi：10.1007/s 00125 -013-3140-5）包含同行评审但未经编辑的补充材料，可供授权用户使用。
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. 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. The online version of this article (doi:10.1007/s00125-013-3140-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
3.7
作者：
Liu LY;Wang F;Zhang XY;Huang P;Lu YB;Wei EQ;Zhang WP
通讯作者：
Zhang WP
DOI：
10.1126/science.1173635
发表时间：
2009-07-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Colman RJ;Anderson RM;Johnson SC;Kastman EK;Kosmatka KJ;Beasley TM;Allison DB;Cruzen C;Simmons HA;Kemnitz JW;Weindruch R
通讯作者：
Weindruch R
影响因子：
4.8
作者：
Brito, Marcia N.;Brito, Nilton A.;Bartness, Timothy J.
通讯作者：
Bartness, Timothy J.
影响因子：
15.9
作者：
Berglund, Eric D.;Vianna, Claudia R.;Elmquist, Joel K.
通讯作者：
Elmquist, Joel K.
DOI：
10.1016/j.bbrc.2008.03.103
发表时间：
2008-06-06
影响因子：
3.1
作者：
Muramatsu, Kazuhiro;Hashimoto, Yukiko;Harada, Akihiro
通讯作者：
Harada, Akihiro