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

• Autor(a) principal: Badenes, Marina
• Data de Publicação: 2019
• Outros Autores: Amin, Abdulbasit, González-García, Ismael, Félix, Inês, Burbridge, Emma, Cavadas, Miguel, Ortega, Francisco José, de Carvalho, Érika, Faísca, Pedro, Carobbio, Stefania, Seixas, Elsa, Pedroso, Dora, Neves-Costa, Ana, Moita, Luís F., Fernández-Real, José Manuel, Vidal-Puig, António, Domingos, Ana, López, Miguel, Adrain, Colin
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.7/910
• topic: iRhom2; ADAM17/TACE; Obesity; Insulin resistance; NAFLD; BAT; Browning; Thermogenesis; UCP1

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 ther- mogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak.