Ucp1, short for uncoupling protein 1, is a key effector in thermogenic adipocytes. It dissipates energy in the form of heat by uncoupling the mitochondrial proton gradient from mitochondrial respiration, playing a central role in brown adipose tissue (BAT) thermogenesis and systemic energy homeostasis [2]. Thermogenic adipocytes, including brown and beige adipocytes, utilize Ucp1-mediated thermogenesis, which could potentially be harnessed as a therapy for metabolic diseases like obesity and type 2 diabetes [1].

Previous views considered Ucp1 as the sole mediator of adipocyte thermogenesis, mainly inferred from germline Ucp1 -/- mice with attenuated thermogenic output. However, mice with inducible adipocyte-selective Ucp1 disruption showed that most can maintain homeothermy in the cold, indicating other thermogenic mechanisms exist. Co-deletion of Ucp1 and creatine kinase b (Ckb) exacerbates cold intolerance, suggesting non-paralogous protein redundancy through Ucp1 and Ckb in promoting cold-induced energy dissipation [3]. In addition, inhibition of SERCA2b impairs Ucp1-independent beige fat thermogenesis in humans, mice, and pigs (lacking functional Ucp1), while enhanced Ca2+ cycling stimulates it, showing a Ucp1-independent thermogenic mechanism in beige fat [4].

In conclusion, Ucp1 is crucial for adipocyte thermogenesis and systemic energy balance. Studies using Ucp1 knockout mouse models have not only revealed its central role in thermogenesis but also helped identify additional non-Ucp1-dependent thermogenic pathways. These findings offer new perspectives for understanding energy metabolism and developing treatments for metabolic disorders such as obesity and type 2 diabetes.