The high prevalence of obesity worldwide has fuelled research to discover new treatments that tackle obesity safely and effectively. Over the last decades, we and others have considered that developing strategies focused on increasing organismal energy expenditure may help fight obesity and its associated comorbidities. For this purpose, our research focused on a gene called Thada. THADA encodes a 220 kDa protein that has been recently reported in Drosophila melanogaster to uncouple the heat dissipation of SERCA from its Ca2+ pumping action. We anticipated that this mechanism could contribute significantly to the energy metabolism in endotherms, such as mammals. We envisaged THADA could contribute to the muscle non-shivering thermogenesis—in addition to sarcolipin, another uncoupler of SERCA. Our working hypothesis was reinforced by the fact that mutations in THADA have been positively selected during the last 45-30K years in the Arctic populations, which the authors of the research and we interpret as a potential adaption to the extreme cold. In this thesis, I have performed in vitro and in vivo approaches and confirmed that the ablation of THADA caused increased ATP hydrolysis and Ca2+ transport efficiency of SERCA and affected cellular bioenergetics in primary skeletal muscle cells. Interestingly, phenotypic characterisation of the Thada KO mice has revealed that the genetic ablation of Thada causes an impairment in the maintenance of core body temperature in response to cold exposure. This effect can only be revealed under specific environmental conditions when the brown adipose tissue (BAT) is cancelled/neutralised. Our physiological data are supported by a robust transcriptomic signature where skeletal muscle, BAT and inguinal subcutaneous white adipose tissue of the Thada KO mice presented primary and compensatory fingerprints associated with the environmental temperatures tested. The findings of this thesis provide evidence of THADA’s contribution to energy homeostasis in mammals and open the possibility of using THADA as a viable therapeutic target to increase basal metabolic rate and hence energy expenditure to tackle obesity.