A Genetic Model to Study the Contribution of Brown and Brite Adipocytes to Metabolism

Abstract

Summary: UCP1-dependent thermogenesis is studied to define new strategies to ameliorate obesity and type 2 diabetes; however, animal models are mostly limited to germline mutations of UCP1, which can effect adaptive changes in UCP1-independent pathways. We develop an inducible mouse model for the sequential ablation of UCP1+ brown and brite/beige adipocytes in adult mice. We demonstrate that activated brown adipocytes can increase systemic energy expenditure (EE) by 30%, while the contribution of brite/beige UCP1+ cells is <5%. Notably, UCP1+ adipocytes do not contribute to circulating FGF21 levels, either at room temperature or after cold exposure. We demonstrate that the FGF21-mediated effects on EE and glucose homeostasis are partially dependent on the presence of UCP1+ cells, while the effect on weight loss is not. In conclusion, acute UCP1+ cell deletion may be a useful model to study the impact of brown and brite/beige adipocytes on metabolism. : Challa et al. develop a mouse model to ablate UCP1+ adipocytes and demonstrate that activated brown adipocytes contribute 30% to energy expenditure (EE), while the contribution of brite/beige cells is low. The effect of FGF21 on EE and glucose homeostasis is in part dependent on the presence of UCP1+ cells. Keywords: UCP1, inducible mouse model, acute brown and brite/beige adipocytes ablation, FGF21