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Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis.
Molecular Metabolism ( IF 8.1 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.molmet.2019.10.006
Marina Badenes 1 , Abdulbasit Amin 2 , Ismael González-García 3 , Inês Félix 4 , Emma Burbridge 1 , Miguel Cavadas 1 , Francisco José Ortega 5 , Érika de Carvalho 1 , Pedro Faísca 1 , Stefania Carobbio 6 , Elsa Seixas 1 , Dora Pedroso 1 , Ana Neves-Costa 1 , Luís F Moita 7 , José Manuel Fernández-Real 5 , António Vidal-Puig 6 , Ana Domingos 8 , Miguel López 3 , Colin Adrain 9
Affiliation  

Objective

Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energy dissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Here we evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in the pathophysiology of metabolic syndrome.

Methods

We challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared their metabolic phenotypes. We also carried out ex vivo assays with primary and immortalized mouse brown adipocytes to establish the autonomy of the effect of loss of iRhom2 on thermogenesis and respiration.

Results

Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improved insulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beige adipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced thermogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak.

Conclusion

Our data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasis during metabolic disease.



中文翻译:

删除 iRhom2 通过增加产热来防止饮食引起的肥胖。

客观的

肥胖是正能量平衡的结果。它可能是由过度的能量消耗引起的,也可能是由于能量消耗减少引起的,这种情况发生在几种情况下,包括棕色脂肪组织 (BAT) 的发育或活化受损时。在这里,我们评估了肿瘤坏死因子 (TNF) 脱落酶 ADAM17/TACE 的必需辅助因子 iRhom2 是否在代谢综合征的病理生理学中发挥作用。

方法

我们通过长期暴露于高脂肪饮食来挑战 WT 与 iRhom2 KO 小鼠的正能量平衡,然后比较它们的代谢表型。我们还对原代和永生化小鼠棕色脂肪细胞进行了体外测定,以确定 iRhom2 缺失对产热和呼吸的影响的自主性。

结果

删除 iRhom2 可保护小鼠免于体重增加、血脂异常、脂肪组织炎症和肝脂肪变性,并在受到高脂肪饮食挑战时改善胰岛素敏感性。至关重要的是,iRhom2 的丢失通过 BAT 激活和米色脂肪细胞募集促进产热,使 iRhom2 KO 小鼠比 WT 动物更有效地消散多余的能量。这种对增强产热的影响在棕色脂肪细胞中是细胞自主的,因为 iRhom2 KO 表现出 UCP1 水平升高和线粒体质子泄漏增加。

结论

我们的数据表明,iRhom2 是产热的负调节因子,在代谢疾病期间在控制脂肪组织稳态中发挥作用。

更新日期:2019-10-31
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