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Deletion of iRhom2 protects against diet-inducedobesity by increasing thermogenesis

Published version
Peer-reviewed

Type

Article

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Authors

Vidal-Puig, Antonio  ORCID logo  https://orcid.org/0000-0003-4220-9577
Carobbio, Stefania 
Badenes, Marina 
Abdulbasit, Amin 
González-García, Ismael 

Abstract

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

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Journal Title

Molecular Metabolism

Conference Name

Journal ISSN

2212-8778

Volume Title

Publisher

Elsevier
Sponsorship
Wellcome Trust strategic award (100574/Z/12/Z) and MRC MDU (MC_UU_12012/2