The giant panda (Ailuropoda melanoleuca) is an iconic bear native to China, famous for eating almost exclusively bamboo. This unusual dietary behavior for a carnivore is enabled by several key adaptations including low physical activity, reduced organ sizes and hypothyroidism leading to lowered energy expenditure. These adaptive phenotypes have been hypothesised to arise from a panda-unique single-nucleotide mutation in the dual-oxidase 2 (DUOX2) gene, involved in thyroid hormone synthesis. To test this hypothesis we created genome edited mice carrying the same point mutation as the panda and investigated its effects on metabolic phenotype. Homozygous mice were 27% smaller than heterozygous and wild-type ones, had 13% lower body mass-adjusted food intake, 55% decreased physical activity, lower mass of kidneys (11%) and brain (5%), lower serum thyroxine (T4: 36%), decreased absolute (12%) and mass-adjusted (5%) daily energy expenditure, and altered gut microbiota. Supplementation with T4 reversed the effects of the mutation. This work uses a state of the art genome editing approach to demonstrate the link between a single-nucleotide mutation in a key endocrine related gene leading to profound adaptive changes in the metabolic phenotype, with great importance in ecology and evolution.