Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis.
Ortega, Francisco José
de Carvalho, Érika
Moita, Luís F
Fernández-Real, José Manuel
MetadataShow full item record
Badenes, M., Amin, A., González-García, I., Félix, I., Burbridge, E., Cavadas, M., Ortega, F. J., et al. (2019). Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis.. Molecular metabolism, 31 67-84. https://doi.org/10.1016/j.molmet.2019.10.006
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.
Obesity, Browning, Thermogenesis, Insulin resistance, bat, Nafld, Adam17/tace, Ucp1, Irhom2
Medical Research Council (MC_UU_12012/2)
Wellcome Trust (100574/Z/12/Z)
European Research Council (647888)
External DOI: https://doi.org/10.1016/j.molmet.2019.10.006
This record's URL: https://www.repository.cam.ac.uk/handle/1810/301961
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/