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Brown and beige adipocytes, collectively known as thermogenic adipocytes, express uncoupling protein 1 (UCP1) to dissipate energy as heat. Enhancing their differentiation and activity increases energy expenditure and is considered a promising strategy for obesity treatment. Adults possess only small amounts of brown/beige fat; thus, promoting the browning of white adipose tissue has emerged as a more practical approach to boost thermogenic capacity. MCU and MICU1 are core components of the mitochondrial calcium uniporter complex, regulating mitochondrial calcium uptake. Their expression correlates with the thermogenic differentiation potential in adipose precursor cells; however, the mechanisms underlying this regulation remain unclear. We demonstrated that simultaneous deletion of MCU and MICU1 impairs brown adipocyte function, whereas co-overexpression (DOE) enhances mitochondrial activity and UCP1 induction in human white preadipocytes during adipogenesis. Loss of both genes in brown preadipocytes leads to structurally abnormal mitochondria, reduced calcium-evoked thermogenic responses, and worsened diet-induced metabolic abnormalities in vivo. These findings suggest that MCU and MICU1 are crucial for the formation of mitochondria and the induction of thermogenic programming during adipocyte differentiation, with significant implications for whole-body metabolic health. Transcriptomic and bioinformatic analyses further identified MAF as a downstream transcription factor mediating this pathway. MAF knockout reduced UCP1 expression, mitochondrial activity, and thermogenesis in DOE cells. Together, our results define an MCU–MICU1–MAF regulatory axis that coordinates mitochondrial function and thermogenic gene expression to promote the formation of thermogenic adipocytes. This mechanism may contribute to improved glucose metabolism and energy homeostasis, offering new insight into the regulation of thermogenic fat and its therapeutic potential for metabolic diseases.