Competitive disadvantage masks growth and metabolic phenotypes in SNORD116 knockout mice

Prader-Willi syndrome (PWS) is characterized by early hypotonia and feeding difficulties, followed by hyperphagia, increased adiposity, and metabolic dysfunction. Although SNORD116 knockout (KO) mice recapitulate several features of PWS, they generally exhibit reduced body weight and adiposity in contrast to the clinical manifestations in PWS patients. Here, we compared heterozygous breeding, which generates mixed-genotype litters containing wild-type (WT) and KO pups, with isolated homozygous breeding, which generates single-genotype litters. Under heterozygous breeding, KO mice exhibited reduced body weight and adiposity, together with no impairment, or even improved glucose tolerance. In contrast, KO mice from isolated homozygous litters developed increased adiposity and impaired glucose tolerance despite remaining lighter than WT. These effects were sex-dependent, with adiposity and metabolic abnormalities generally more significant in males than in females. Food intake was also influenced by age, sex, and breeding condition. Increased absolute food intake was most evident during the juvenile period in KO mice from isolated homozygous litters, particularly in males, whereas adult KO mice did not show consistent hyperphagia. Cross-fostering, large-litter, and CD1 foster-nursing experiments further demonstrated that early-life nursing conditions modify subsequent growth, adiposity, and metabolism. Moreover, pre-weaning KO pups exhibited reduced spontaneous movement, weaker grip strength, and lower muscle mass, supporting a potential competitive disadvantage during lactation. These findings indicate that early-life nutritional conditions may mask genotype-associated abnormalities, with isolated homozygous breeding representing a suitable model for investigating PWS phenotypes.