Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis.
Ortega, Francisco José
de Carvalho, Érika
Moita, Luís F
Fernández-Real, José Manuel
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Vidal-Puig, A., Carobbio, S., Badenes, M., Amin, A., González-García, I., Félix, I., Burbridge, E., et al. (2020). Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis.. Molecular Metabolism https://doi.org/10.17863/CAM.48180
Objective:Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energydissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Herewe evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in thepathophysiology 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 theirmetabolic phenotypes. We also carried outex vivoassays with primary and immortalized mouse brown adipocytes to establish the autonomy ofthe 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 improvedinsulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beigeadipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced ther-mogenesis 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 homeostasisduring metabolic disease.
Wellcome Trust strategic award (100574/Z/12/Z) and MRC MDU (MC_UU_12012/2).
Wellcome Trust (208363/Z/17/Z)
This record's DOI: https://doi.org/10.17863/CAM.48180
This record's URL: https://www.repository.cam.ac.uk/handle/1810/301103
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/