AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue.
AMP-Activated Protein Kinase (AMPK) Regulates Energy Metabolism through Modulating Thermogenesis in Adipose Tissue.
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AMP 激活蛋白激酶 (AMPK) 通过调节脂肪组织中的产热来调节能量代谢
DOI：
10.3389/fphys.2018.00122
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发表时间：
2018
影响因子：
4
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Wu L;Zhang L;Li B;Jiang H;Duan Y;Xie Z;Shuai L;Li J;Li J
当多余的能量积聚在白色脂肪组织（WAT）中时，肥胖就会发生，而专门通过产热耗散能量的棕色脂肪组织（BAT）则有效地抵消肥胖。白色脂肪细胞在各种刺激下，如冷暴露下，可转化为产热的“褐色样”细胞（米色细胞; WAT布朗宁）。AMP活化蛋白激酶（AMPK）是一种重要的能量传感器，调节多种组织的能量代谢。然而，AMPK在脂肪组织功能中的作用，特别是在WAT布朗宁过程中的作用还没有完全了解。为了阐明脂肪细胞AMPK对能量代谢的影响，我们产生了脂联素-Cre驱动的脂肪组织特异性AMPK α1/α2 KO小鼠（AKO）。这些AKO小鼠不耐冷，它们的腹股沟WAT表现出线粒体完整性和生物发生受损，并且在冷暴露后产热标记物的表达减少。高脂饮食（HFD）喂养的AKO小鼠表现出肥胖增加，肝脂肪变性和纤维化加重，葡萄糖耐量和胰岛素敏感性受损。同时，AKO小鼠在基础条件下和用β3-肾上腺素能受体激动剂CL 316，243刺激后的能量消耗和耗氧量均显著降低。相比之下，我们发现在HFD喂养的肥胖小鼠模型中，A-769662的慢性AMPK激活可防止肥胖和相关的代谢功能障碍。A-769662缓解HFD诱导的葡萄糖耐受不良，并降低体重增加和WAT扩张。值得注意的是，A-769662增加了HFD喂养小鼠的能量消耗和耐冷性。A-769662处理还诱导了HFD喂养小鼠腹股沟脂肪贮库的布朗宁过程。同样，A-769662通过AMPK信号通路增强分化的腹股沟基质血管部分（SVF）细胞的产热作用。总之，缺乏脂肪细胞AMPKα分别诱导了对寒冷和营养超负荷的产热损伤和肥胖，而A-769662的慢性AMPK激活促进了腹股沟WAT中的WAT布朗宁，并保护免受HFD诱导的肥胖和相关代谢功能障碍。这些发现揭示了脂肪细胞AMPK在调节腹股沟WAT中的布朗宁过程和维持能量稳态中的重要作用，这表明脂肪细胞AMPK的靶向活化可能是抗肥胖治疗的有希望的策略。
Obesity occurs when excess energy accumulates in white adipose tissue (WAT), whereas brown adipose tissue (BAT), which is specialized in dissipating energy through thermogenesis, potently counteracts obesity. White adipocytes can be converted to thermogenic “brown-like” cells (beige cells; WAT browning) under various stimuli, such as cold exposure. AMP-activated protein kinase (AMPK) is a crucial energy sensor that regulates energy metabolism in multiple tissues. However, the role of AMPK in adipose tissue function, especially in the WAT browning process, is not fully understood. To illuminate the effect of adipocyte AMPK on energy metabolism, we generated Adiponectin-Cre-driven adipose tissue-specific AMPK α1/α2 KO mice (AKO). These AKO mice were cold intolerant and their inguinal WAT displayed impaired mitochondrial integrity and biogenesis, and reduced expression of thermogenic markers upon cold exposure. High-fat-diet (HFD)-fed AKO mice exhibited increased adiposity and exacerbated hepatic steatosis and fibrosis and impaired glucose tolerance and insulin sensitivity. Meanwhile, energy expenditure and oxygen consumption were markedly decreased in the AKO mice both in basal conditions and after stimulation with a β3-adrenergic receptor agonist, CL 316,243. In contrast, we found that in HFD-fed obese mouse model, chronic AMPK activation by A-769662 protected against obesity and related metabolic dysfunction. A-769662 alleviated HFD-induced glucose intolerance and reduced body weight gain and WAT expansion. Notably, A-769662 increased energy expenditure and cold tolerance in HFD-fed mice. A-769662 treatment also induced the browning process in the inguinal fat depot of HFD-fed mice. Likewise, A-769662 enhanced thermogenesis in differentiated inguinal stromal vascular fraction (SVF) cells via AMPK signaling pathway. In summary, a lack of adipocyte AMPKα induced thermogenic impairment and obesity in response to cold and nutrient-overload, respectively, whereas chronic AMPK activation by A-769662 promoted WAT browning in inguinal WAT and protected against HFD-induced obesity and related metabolic dysfunction. These findings reveal a vital role for adipocyte AMPK in regulating the browning process in inguinal WAT and in maintaining energy homeostasis, which suggests that the targeted activation of adipocyte AMPK may be a promising strategy for anti-obesity therapy.
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影响因子：
5.2
作者：
Collins S
通讯作者：
Collins S
影响因子：
3.5
作者：
CARLING, D;ZAMMIT, VA;HARDIE, DG
通讯作者：
HARDIE, DG
影响因子：
4.8
作者：
Fentz, Joachim;Kjobsted, Rasmus;Wojtaszewski, Jorgen F. P.
通讯作者：
Wojtaszewski, Jorgen F. P.
DOI：
10.1016/j.bbrc.2005.11.159
发表时间：
2006-02-03
影响因子：
3.1
作者：
Dagon, Y;Avraham, Y;Berry, EM
通讯作者：
Berry, EM
影响因子：
6.5
作者：
Gaidhu, Mandeep P.;Fediuc, Sergiu;Ceddia, Rolando B.
通讯作者：
Ceddia, Rolando B.