Cox10-mediated mitochondrial respiration in brown adipocytes regulates adaptive thermogenesis and systemic metabolism

Mitochondrial respiration is essential for Ucp1-mediated thermogenesis in brown adipocytes, where heat production depends on oxygen-driven mitochondrial activity. To define the role of complex IV, we generated brown-adipocyte-specific Cox10-knockout mice (Cox10 BKO ), as Cox10 is required for cytochrome c oxidase assembly. Cox10-deficient brown adipocytes exhibited markedly reduced complex IV activity and impaired Ucp1-dependent thermogenesis. Although ATF4 signaling was strongly induced, the alternative ATF4-dependent thermogenic pathway failed due to suppression of global protein synthesis, consistent with severe mitochondrial stress and reduced ribosomal gene expression. Unexpectedly, Cox10 BKO mice housed at room temperature or thermoneutrality were protected against high-fat-diet-induced obesity and insulin resistance. These findings demonstrate that brown adipocytes regulate systemic metabolic homeostasis independently of canonical thermogenic function and suggest that respiration-deficient brown fat may promote metabolic fitness through endocrine or metabolic signaling mechanisms.