Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice.
Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice.
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GDF15和FGF21的遗传缺失对高脂喂养小鼠的体重，肝脂肪变性和胰岛素抵抗具有适度的影响。
DOI：
10.1016/j.molmet.2022.101589
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发表时间：
2022-11
影响因子：
8.1
通讯作者：
Savage, David B.
中科院分区：
文献类型：
--
作者：
Patel, Satish;Haider, Afreen;Alvarez-Guaita, Anna;Bidault, Guillaume;Moustafa, Julia Sarah El-Sayed;Guiu-Jurado, Esther;Tadross, John A.;Warner, James;Harrison, James;Virtue, Samuel;Scurria, Fabio;Zvetkova, Ilona;Bluher, Matthias;Small, Kerrin S.;O'Rahilly, Stephen;Savage, David B.
人类和小鼠的肥胖与两种对细胞应激反应的激素水平升高有关，即GDF 15和FGF 21。这些中的每一个的过度表达与体重减轻和有益的代谢变化相关，但是它们从哪里分泌以及在过度喂养的背景下它们在生理上需要什么仍然不清楚。在这里，我们使用组织选择性敲除小鼠模型和人类转录组学来确定肥胖症中循环GDF 15的来源。然后，我们生成并表征了GDF 15/FGF 21双敲除小鼠的代谢表型。在肥胖状态下，循环GDF 15和FGF 21都主要来源于肝脏，而不是脂肪组织或骨骼肌。FGF 21和GDF 15的组合全身缺失不会导致响应于高脂肪喂养的任何额外的体重增加，但它确实导致比GDF 15单敲除小鼠中所见的显著更大的肝脂肪变性和胰岛素抵抗。总的来说，这些数据表明，过度喂养激活了肝脏中的应激反应，这是GDF 15和FGF 21全身性升高的主要来源。这些激素然后激活减少这种代谢压力的途径。GDF 15敲除小鼠在高脂肪饮食中显示出更大的肥胖。肝细胞是小鼠中高脂饮食诱导的GDF 15和FGF 21的主要来源。GDF 15和FGF 21协同保护免受肥胖诱导的脂肪肝。GDF 15和FGF 21的缺失加剧小鼠的胰岛素抵抗。
Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear. Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity. We then generated and characterized the metabolic phenotypes of GDF15/FGF21 double knockout mice. Circulating GDF15 and FGF21 are both largely derived from the liver, rather than adipose tissue or skeletal muscle, in obese states. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in response to high fat feeding but it does result in significantly greater hepatic steatosis and insulin resistance than that seen in GDF15 single knockout mice. Collectively the data suggest that overfeeding activates a stress response in the liver which is the major source of systemic rises in GDF15 and FGF21. These hormones then activate pathways which reduce this metabolic stress. GDF15 knockout mice display greater obesity on a high fat diet. Hepatocytes are the major source of high fat diet-induced GDF15 and FGF21 in mice. GDF15 and FGF21 synergistically protect against obesity-induced hepatosteatosis. Deletion of GDF15 and FGF21 exacerbate insulin resistance in mice.
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影响因子：
82.9
作者：
Emmerson, Paul J.;Wang, Feng;Wu, Xinle
通讯作者：
Wu, Xinle
影响因子：
4.3
作者：
Cinti S
通讯作者：
Cinti S
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作者：
Bunney PE;Zink AN;Holm AA;Billington CJ;Kotz CM
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Kotz CM
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作者：
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Shong, Minho
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作者：
Arner, Peter;Ryden, Mikael
通讯作者：
Ryden, Mikael