Blubber Thickening Driven by UCP1 Inactivation: Insights from a Cetacean‐Like Transgenic Mouse Model

Cetaceans possess thick blubber, a specialized adipose tissue essential for thermal insulation, a streamlined body form, energy storage, and buoyancy. However, the mechanisms that underpin this adaptation are not yet fully understood. Here, we found that uncoupling protein 1 (UCP1) of cetaceans has undergone significant evolutionary relaxation. A transgenic mouse model with cetacean-like UCP1 inactivation revealed a pronounced obesity phenotype, including expanded brown adipose tissue (BAT) and increased white adipose tissue (WAT) adipocyte hyperplasia. Histological, metabolic, and physiological assessments showed reduced lipolysis, impaired glucose metabolism, and upregulated lipid metabolism pathways in BAT. Additionally, gut microbiome analysis indicated an increased Firmicutes/Bacteroidetes ratio, suggesting enhanced energy absorption and weight gain. Comparison with traditional UCP1-KO mice further revealed that the unique mutations in cetacean UCP1 could be the molecular basis for observed fat accumulation phenotype. Our findings provide novel insights into the evolutionary mechanisms underlying blubber thickening in the secondary aquatic adaptation of cetaceans.