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

ABSTRACT: Mitochondrial respiration is essential for Ucp1-mediated thermogenesis in brown adipocytes, where heat is produced through oxygen-dependent mitochondrial activity. To investigate the role of complex IV in this process, we generated brown adipocyte–specific Cox10 knockout mice (Cox10BKO), as COX10 is required for the assembly of cytochrome c oxidase (complex IV). Cox10-deficient brown adipocytes displayed markedly reduced complex IV activity and were unable to support Ucp1-dependent thermogenesis. Previous studies have shown that disruption of mtDNA-encoded electron transport chain (ETC) gene expression abolishes the Ucp1-mediated thermogenesis but induces an alternative, ATF4-driven thermogenic program involving increased protein turnover. In Cox10-deficient brown adipocytes, ATF4 target genes were strongly induced; however, this alternative thermogenic pathway did not occur because global protein synthesis was suppressed, likely reflecting severe mitochondrial stress. Interestingly, the Cox10BKO mice were protected against high-fat-diet-induced metabolic abnormalities. These findings reveal that brown adipocytes can influence whole-body metabolic homeostasis independently of their canonical thermogenic function, suggesting previously unrecognized endocrine or metabolic roles for brown fat.

ORGANISM(S): Mus musculus

PROVIDER: GSE316308 | GEO | 2026/05/27

REPOSITORIES: GEO

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Project description:Non-shivering thermogenesis in adipocytes is mediated by brown adipose tissue, purportedly through the sole action of uncoupling protein 1 (UCP1). The physiological relevance of UCP1-dependent thermogenesis has primarily been inferred from the attenuation of thermogenic output of mice genetically lacking Ucp1 from birth (germline Ucp1-/-). However, germline Ucp1-/- mice harbor secondary changes within brown adipose tissue beyond UCP1, such as reduced electron transport chain abundance. We show here that these secondary changes also encompass reduced expression of genes regulating fuel liberation, changes that would attenuate the capacity of any thermogenic pathway. Therefore, the quantitative contribution of UCP1-dependent and -independent thermogenesis is not fully understood. To mitigate the potentially confounding ancillary changes to brown adipose tissue of germline Ucp1-/- mice, we constructed mice with inducible adipocyte-selective disruption of Ucp1. We find that, while germline Ucp1-/- mice succumb to cold-induced hypothermia with complete penetrance, most mice with inducible deletion of Ucp1 maintain homeothermy in the cold. However, inducible adipocyte-selective co-deletion of Ucp1 and creatine kinase B (Ckb, an effector of UCP1-independent thermogenesis) exacerbates cold-intolerance, indicative of a negative genetic interaction and thus a parallel thermogenic function. We find no evidence for impairments in insulation or non-shivering thermogenesis in skeletal muscle that would drive this phenotype. Furthermore, following UCP1 deletion or UCP1/CKB co-deletion from mature adipocytes, moderate cold exposure triggers the regeneration of mature adipocytes that coordinately restore UCP1 and CKB to brown adipose tissue, providing further evidence of their parallel thermogenic relationship. Our findings suggest that thermogenic adipocytes utilize non-paralogous protein redundancy – through UCP1 and CKB – to promote cold-induced energy dissipation.

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

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