Metformin opposes impaired AMPK and SIRT1 function and deleterious changes in core clock protein expression in white adipose tissue of genetically-obese db/db mice
Metformin opposes impaired AMPK and SIRT1 function and deleterious changes in core clock protein expression in white adipose tissue of genetically-obese db/db mice
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DOI：
10.1111/j.1463-1326.2011.01466.x
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发表时间：
2011-12-01
影响因子：
5.8
通讯作者：
Sugden, M. C.
中科院分区：
文献类型：
--
作者：
Caton, P. W.;Kieswich, J.;Sugden, M. C.
目的：AMPK激活肝脏和骨骼肌中的SIRT 1。昼夜节律功能受损与肥胖的发展有关。SIRT 1调节昼夜节律功能，并在肥胖患者的白色脂肪组织（WAT）中受到抑制。我们研究了AMPK和SIRT 1在调节肥胖db/db小鼠和高脂饮食（HFD）小鼠WAT中的昼夜节律成分中的潜在作用，并研究了二甲双胍介导的AMPK激活是否对抗WAT时钟机制中的任何有害变化。方法：db/+和db/db小鼠给予二甲双胍（250 mg/kg/天; 7天）。另外，小鼠喂食HFD 16周。将3 T3-L1脂肪细胞分别与二甲双胍、EX 527或FK 866（SIRT 1和NAMPT的抑制剂）孵育。结果：db/db和HFD小鼠WAT中AMPK活性、NAMPT表达和SIRT 1表达均降低，与昼夜节律核心成分CLOCK和BMAL 1的表达抑制相关。Ppar的表达。成脂抑制因子Irf 3和Irf 4也被抑制。二甲双胍增加db/db小鼠WAT和二甲双胍处理的脂肪细胞中AMPK活性，增加NAMPT，SIRT 1和昼夜节律组分表达。结论：db/db和HFD小鼠AMPK-SIRT 1信号通路的减少影响WAT昼夜节律功能，导致脂质调节失调，有利于肥胖表型的形成。代谢酶通过AMPK-NAMPT-SIRT 1介导的生物钟组分的变化介导远离脂质积累的表型转变，支持肥胖症的慢性治疗方法。
Aim: AMPK activates SIRT1 in liver and skeletal muscle. Impaired circadian function is associated with development of obesity. SIRT1 regulates circadian function and is suppressed in white adipose tissue (WAT) of obese patients. We examined the potential role of AMPK and SIRT1 in regulation of circadian components in WAT of obese db/db mice and in mice fed a high-fat diet (HFD), and investigated whether metformin-mediated activation of AMPK opposed any deleterious changes in the WAT clock mechanism.Methods: db/+ and db/db mice were administered metformin (250 mg/kg/day; 7 days). Separately, mice were fed HFD for 16-weeks. 3T3-L1 adipocytes were incubated with metformin, EX527 or FK866, inhibitors of SIRT1 and NAMPT, respectively. Gene and protein expression were measured by qRT-PCR and immunoblotting.Results: AMPK activity, NAMPT expression and SIRT1 expression were decreased in WAT of db/db and HFD mice, in association with suppressed expression of the core circadian components CLOCK and BMAL1. Expression of Ppar. and the adipogenic repressors Irf3 and Irf4 were also suppressed. Metformin increased AMPK activity in WAT of db/db mice and in metformin-treated adipocytes, with increased NAMPT, SIRT1 and circadian component expression. Metformin-mediated induction of Clock mRNA in adipocytes was blocked by inhibition of NAMPT and SIRT1.Conclusions: Decreased AMPK-SIRT1 signalling in db/db and HFD mice impacts WAT circadian function causing dysregulated lipid regulation, favouring an obese phenotype. Metformin mediates a phenotypic shift away from lipid accretion through AMPK-NAMPT-SIRT1 mediated changes in clock components, supporting chronotherapeutic treatment approaches for obesity.