Milk lacking α-casein leads to permanent reduction in body size in mice

The major physiological function of milk is the transport of amino acids, carbohydrates, lipids and minerals to mammalian offspring. Caseins, the major milk proteins, are secreted in the form of a micelle consisting of protein and calcium-phosphate. We have analysed the role of the milk protein alpha-casein by inactivating the corresponding gene in mice. Absence of alpha-casein protein significantly curtails secretion of other milk proteins and calcium-phosphate, suggesting a role for alpha-casein in the establishment of casein micelles. In contrast, secretion of albumin, which is not synthesized in the mammary epithelium, into milk is not reduced. The absence of alpha-casein also significantly inhibits transcription of the other casein genes. alpha-Casein deficiency severely delays pup growth during lactation and results in a life-long body size reduction compared to control animals, but has only transient effects on physical and behavioural development of the pups. The data support a critical role for alpha-casein in casein micelle assembly. The results also confirm lactation as a critical window of metabolic programming and suggest milk protein concentration as a decisive factor in determining adult body weight.