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

Kolb AF, Huber RC, Lillico SG, Carlisle A, Robinson CJ, Neil C, Petrie L, Sorensen DB, Olsson IA, Whitelaw CB - PLoS ONE (2011)

Bottom Line: In contrast, secretion of albumin, which is not synthesized in the mammary epithelium, into milk is not reduced.The absence of α-casein also significantly inhibits transcription of the other casein genes. α-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 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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Recognition Group, Hannah Research Institute, Ayr, United Kingdom. a.kolb@abdn.ac.uk

ABSTRACT
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 α-casein by inactivating the corresponding gene in mice. Absence of α-casein protein significantly curtails secretion of other milk proteins and calcium-phosphate, suggesting a role for α-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 α-casein also significantly inhibits transcription of the other casein genes. α-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 α-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.

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Impact of α-casein deficient milk on pup growth.Panel A: Growth curve of three different groups of mice during lactation (G1: wild-type pups nursed by wild-type dams n = 34; G2: wild-type pups nursed by α-casein deficient [−/−] dams, n = 25; and G3: heterozygous pups nursed by wild-type dams, n = 22). Values shown are +/− standard deviation. All weight differences between group G2 vs. G1 and G3 were significant from day 7 (p<0.001) as assessed by ANOVA. Panel B: Percentage weight gain throughout different stages of life for the three experimental groups. The weight of individual mice was compared on two days (as indicated: e.g. 1/3 corresponds to the interval between day 3 and day 1 of life) and the percent weight increase was recorded. The average for all mice in the three experimental groups is shown for consecutive time periods. Panel C: Growth curve of mice in the three groups over the first 6 months of life. Mice nursed by α-casein deficient dams show a consistent growth deficiency. Panel D: Growth curve of mice in the three groups of mice over the first 6 months of life separated by gender. Error bars represent standard deviations.
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pone-0021775-g009: Impact of α-casein deficient milk on pup growth.Panel A: Growth curve of three different groups of mice during lactation (G1: wild-type pups nursed by wild-type dams n = 34; G2: wild-type pups nursed by α-casein deficient [−/−] dams, n = 25; and G3: heterozygous pups nursed by wild-type dams, n = 22). Values shown are +/− standard deviation. All weight differences between group G2 vs. G1 and G3 were significant from day 7 (p<0.001) as assessed by ANOVA. Panel B: Percentage weight gain throughout different stages of life for the three experimental groups. The weight of individual mice was compared on two days (as indicated: e.g. 1/3 corresponds to the interval between day 3 and day 1 of life) and the percent weight increase was recorded. The average for all mice in the three experimental groups is shown for consecutive time periods. Panel C: Growth curve of mice in the three groups over the first 6 months of life. Mice nursed by α-casein deficient dams show a consistent growth deficiency. Panel D: Growth curve of mice in the three groups of mice over the first 6 months of life separated by gender. Error bars represent standard deviations.

Mentions: Weight gain during lactation was significantly reduced in offspring nursed by α-casein deficient dams (p<0.001 for all comparisons of offspring nursed by α-casein deficient dams with the other two groups after day 3). This effect was seen when α-casein deficient dams nursed their own pups and if the offspring of wild-type mice was nursed by deficient dams. This demonstrates that the effect is mediated by the genotype of the nursing female. This effect was also seen in two further litters after breeding of the α-casein deficient mice onto a CD1 background (Kolb et al., unpublished). All females were able to nurse their pups, as indicated by the presence of milk in the stomach (‘milk spot’) in all groups of pups (Table 3). However, by day 6, pups nursed by α-casein deficient dams were visibly emaciated (Fig. 8a) in comparison with pups nursed by control dams (Fig. 8b). By mid-lactation offspring nursed by α-casein deficient mice are significantly smaller than offspring nursed by control dams (Fig. 8c). Pre-weaning mortality was low in all groups and unaffected by dam genotype. Weighing of individual pups throughout lactation demonstrates that offspring nursed by α-casein deficient dams only reach a weight of around 3 g by the end of lactation, whereas pups nursed by control dams weigh around 12 g (Fig. 8d and Fig. 9a). After weaning mice were maintained on a standard chow diet ad libitum. Offspring nursed by α-casein deficient dams display a significantly accelerated growth with respect to the control group between weaning and day 50 of life (Fig. 9b and 10). However, this brief growth spurt is insufficient to bring the weight of pups nursed by α-casein deficient dams up to the weight of control animals in the long term (Fig. 9c). The difference in weight is displayed in both sexes (Fig. 9d).


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

Kolb AF, Huber RC, Lillico SG, Carlisle A, Robinson CJ, Neil C, Petrie L, Sorensen DB, Olsson IA, Whitelaw CB - PLoS ONE (2011)

Impact of α-casein deficient milk on pup growth.Panel A: Growth curve of three different groups of mice during lactation (G1: wild-type pups nursed by wild-type dams n = 34; G2: wild-type pups nursed by α-casein deficient [−/−] dams, n = 25; and G3: heterozygous pups nursed by wild-type dams, n = 22). Values shown are +/− standard deviation. All weight differences between group G2 vs. G1 and G3 were significant from day 7 (p<0.001) as assessed by ANOVA. Panel B: Percentage weight gain throughout different stages of life for the three experimental groups. The weight of individual mice was compared on two days (as indicated: e.g. 1/3 corresponds to the interval between day 3 and day 1 of life) and the percent weight increase was recorded. The average for all mice in the three experimental groups is shown for consecutive time periods. Panel C: Growth curve of mice in the three groups over the first 6 months of life. Mice nursed by α-casein deficient dams show a consistent growth deficiency. Panel D: Growth curve of mice in the three groups of mice over the first 6 months of life separated by gender. Error bars represent standard deviations.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3138747&req=5

pone-0021775-g009: Impact of α-casein deficient milk on pup growth.Panel A: Growth curve of three different groups of mice during lactation (G1: wild-type pups nursed by wild-type dams n = 34; G2: wild-type pups nursed by α-casein deficient [−/−] dams, n = 25; and G3: heterozygous pups nursed by wild-type dams, n = 22). Values shown are +/− standard deviation. All weight differences between group G2 vs. G1 and G3 were significant from day 7 (p<0.001) as assessed by ANOVA. Panel B: Percentage weight gain throughout different stages of life for the three experimental groups. The weight of individual mice was compared on two days (as indicated: e.g. 1/3 corresponds to the interval between day 3 and day 1 of life) and the percent weight increase was recorded. The average for all mice in the three experimental groups is shown for consecutive time periods. Panel C: Growth curve of mice in the three groups over the first 6 months of life. Mice nursed by α-casein deficient dams show a consistent growth deficiency. Panel D: Growth curve of mice in the three groups of mice over the first 6 months of life separated by gender. Error bars represent standard deviations.
Mentions: Weight gain during lactation was significantly reduced in offspring nursed by α-casein deficient dams (p<0.001 for all comparisons of offspring nursed by α-casein deficient dams with the other two groups after day 3). This effect was seen when α-casein deficient dams nursed their own pups and if the offspring of wild-type mice was nursed by deficient dams. This demonstrates that the effect is mediated by the genotype of the nursing female. This effect was also seen in two further litters after breeding of the α-casein deficient mice onto a CD1 background (Kolb et al., unpublished). All females were able to nurse their pups, as indicated by the presence of milk in the stomach (‘milk spot’) in all groups of pups (Table 3). However, by day 6, pups nursed by α-casein deficient dams were visibly emaciated (Fig. 8a) in comparison with pups nursed by control dams (Fig. 8b). By mid-lactation offspring nursed by α-casein deficient mice are significantly smaller than offspring nursed by control dams (Fig. 8c). Pre-weaning mortality was low in all groups and unaffected by dam genotype. Weighing of individual pups throughout lactation demonstrates that offspring nursed by α-casein deficient dams only reach a weight of around 3 g by the end of lactation, whereas pups nursed by control dams weigh around 12 g (Fig. 8d and Fig. 9a). After weaning mice were maintained on a standard chow diet ad libitum. Offspring nursed by α-casein deficient dams display a significantly accelerated growth with respect to the control group between weaning and day 50 of life (Fig. 9b and 10). However, this brief growth spurt is insufficient to bring the weight of pups nursed by α-casein deficient dams up to the weight of control animals in the long term (Fig. 9c). The difference in weight is displayed in both sexes (Fig. 9d).

Bottom Line: In contrast, secretion of albumin, which is not synthesized in the mammary epithelium, into milk is not reduced.The absence of α-casein also significantly inhibits transcription of the other casein genes. α-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 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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Recognition Group, Hannah Research Institute, Ayr, United Kingdom. a.kolb@abdn.ac.uk

ABSTRACT
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 α-casein by inactivating the corresponding gene in mice. Absence of α-casein protein significantly curtails secretion of other milk proteins and calcium-phosphate, suggesting a role for α-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 α-casein also significantly inhibits transcription of the other casein genes. α-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 α-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.

Show MeSH
Related in: MedlinePlus