Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis

Abstract

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

The authors thank the Animal, Mouse Transgenics, Histopathology, Flow cytometry and the Antibody units of the Instituto Gulbenkian de Ciência. We thank Moises Mallo and Ana Nóvoa for advice and help in the generation of FLAG-iRhom2 mutant mice. We thank Jorge Ruas for advice concerning ex vivo primary adipocyte culture. C.A. acknowledges the support of Fundação Calouste Gulbenkian, Worldwide Cancer Research (14–1289), a Marie Curie Career Integration Grant (project no. 618769), Fundação para a Ciência e Tecnologia (FCT, SFRH/BCC/52507/2014; PTDC/BEX-BCM/3015/2014; LISBOA-01–0145-FEDER-031330). M.C. acknowledges the support of the FCT grant (SFRH/BPD/117216/2016). This work was developed with the support of the research infrastructure Congento, project LISBOA-01–0145-FEDER-022170, co-financed by Lisboa Regional Operational Programme (Lisboa 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and Foundation for Science and Technology (Portugal). M.L. was funded by Xunta de Galicia (2016-PG068), Ministerio de Economía y Competitividad (MINECO; SRTI2018-101840-B-I00) and Atresmedia. L.F.M. is an FCT Investigator and is supported by the European Community Horizon 2020 (ERC-2014-CoG 647888-iPROTECTION) and FCT (FCT: PTDC/BIM-MEC/4665/2014). S.C. and A.V.P. were funded by the Wellcome Trust strategic award (100574/Z/12/Z) and MRC MDU (MC_UU_12012/2)