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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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Analysis of milk calcium and phosphate levels and milk protein gene expression.Panel A: Calcium and phosphate content of mouse milk was determined as indicated in the methods section. Concentrations are given in nM. Panel B: Quantitative PCR analysis of α-casein and β-casein gene expression. cDNA derived from representative wild-type, heterozygous [+/−] and homozygous [−/−] α-casein deficient mice was analysed using primer pairs specific for α-casein, β-casein and the reference gene GAPDH. Expression of the casein genes was correlated with the reference gene and is expressed as pg casein/pg GAPDH. Panel C: Quantitative PCR analysis of γ-casein and κ-casein gene expression. Expression of the γ and κ-casein genes was correlated with the reference gene and is expressed as pg casein/pg GAPDH. Panel D: Correlation of casein gene expression in wild type [+/+], heterozygous [+/−] and α-casein deficient mice [−/−] using quantitative PCR. Casein gene expression was correlated with the expression of the reference gene β-actin. Quantification of α-casein was done in 3 [+/+], 7 [+/−] and 5 [−/−] mice. Quantification of β-casein was done in 3 [+/+], 8 [+/−] and 4 [−/−] mice. Quantification of γ- and k-casein was done in 3 [+/+], 3 [+/−] and 3 [−/−] mice. Expression in heterozygous and α-casein deficient mice is presented as percentage of median casein gene expression in wild-type control mice [+/+] (set to 100%). Error bars represent standard deviations. For comparisons against wild-type mice in a one-way ANOVA p<0.05 is indicated by *, p<0.01 by **, and p<0.001 by ***. Exact p values are presented in table 6.
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pone-0021775-g005: Analysis of milk calcium and phosphate levels and milk protein gene expression.Panel A: Calcium and phosphate content of mouse milk was determined as indicated in the methods section. Concentrations are given in nM. Panel B: Quantitative PCR analysis of α-casein and β-casein gene expression. cDNA derived from representative wild-type, heterozygous [+/−] and homozygous [−/−] α-casein deficient mice was analysed using primer pairs specific for α-casein, β-casein and the reference gene GAPDH. Expression of the casein genes was correlated with the reference gene and is expressed as pg casein/pg GAPDH. Panel C: Quantitative PCR analysis of γ-casein and κ-casein gene expression. Expression of the γ and κ-casein genes was correlated with the reference gene and is expressed as pg casein/pg GAPDH. Panel D: Correlation of casein gene expression in wild type [+/+], heterozygous [+/−] and α-casein deficient mice [−/−] using quantitative PCR. Casein gene expression was correlated with the expression of the reference gene β-actin. Quantification of α-casein was done in 3 [+/+], 7 [+/−] and 5 [−/−] mice. Quantification of β-casein was done in 3 [+/+], 8 [+/−] and 4 [−/−] mice. Quantification of γ- and k-casein was done in 3 [+/+], 3 [+/−] and 3 [−/−] mice. Expression in heterozygous and α-casein deficient mice is presented as percentage of median casein gene expression in wild-type control mice [+/+] (set to 100%). Error bars represent standard deviations. For comparisons against wild-type mice in a one-way ANOVA p<0.05 is indicated by *, p<0.01 by **, and p<0.001 by ***. Exact p values are presented in table 6.

Mentions: The caseins are important for ion transport, mainly calcium and phosphate [35], [36]. Not surprisingly we therefore find that the lower casein protein levels in α-casein deficient mice are accompanied by a significantly lower concentration of calcium and phosphate in milk (reduced by around 90% compared to milk derived from wild-type animals; Fig. 5a).


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)

Analysis of milk calcium and phosphate levels and milk protein gene expression.Panel A: Calcium and phosphate content of mouse milk was determined as indicated in the methods section. Concentrations are given in nM. Panel B: Quantitative PCR analysis of α-casein and β-casein gene expression. cDNA derived from representative wild-type, heterozygous [+/−] and homozygous [−/−] α-casein deficient mice was analysed using primer pairs specific for α-casein, β-casein and the reference gene GAPDH. Expression of the casein genes was correlated with the reference gene and is expressed as pg casein/pg GAPDH. Panel C: Quantitative PCR analysis of γ-casein and κ-casein gene expression. Expression of the γ and κ-casein genes was correlated with the reference gene and is expressed as pg casein/pg GAPDH. Panel D: Correlation of casein gene expression in wild type [+/+], heterozygous [+/−] and α-casein deficient mice [−/−] using quantitative PCR. Casein gene expression was correlated with the expression of the reference gene β-actin. Quantification of α-casein was done in 3 [+/+], 7 [+/−] and 5 [−/−] mice. Quantification of β-casein was done in 3 [+/+], 8 [+/−] and 4 [−/−] mice. Quantification of γ- and k-casein was done in 3 [+/+], 3 [+/−] and 3 [−/−] mice. Expression in heterozygous and α-casein deficient mice is presented as percentage of median casein gene expression in wild-type control mice [+/+] (set to 100%). Error bars represent standard deviations. For comparisons against wild-type mice in a one-way ANOVA p<0.05 is indicated by *, p<0.01 by **, and p<0.001 by ***. Exact p values are presented in table 6.
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Related In: Results  -  Collection

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pone-0021775-g005: Analysis of milk calcium and phosphate levels and milk protein gene expression.Panel A: Calcium and phosphate content of mouse milk was determined as indicated in the methods section. Concentrations are given in nM. Panel B: Quantitative PCR analysis of α-casein and β-casein gene expression. cDNA derived from representative wild-type, heterozygous [+/−] and homozygous [−/−] α-casein deficient mice was analysed using primer pairs specific for α-casein, β-casein and the reference gene GAPDH. Expression of the casein genes was correlated with the reference gene and is expressed as pg casein/pg GAPDH. Panel C: Quantitative PCR analysis of γ-casein and κ-casein gene expression. Expression of the γ and κ-casein genes was correlated with the reference gene and is expressed as pg casein/pg GAPDH. Panel D: Correlation of casein gene expression in wild type [+/+], heterozygous [+/−] and α-casein deficient mice [−/−] using quantitative PCR. Casein gene expression was correlated with the expression of the reference gene β-actin. Quantification of α-casein was done in 3 [+/+], 7 [+/−] and 5 [−/−] mice. Quantification of β-casein was done in 3 [+/+], 8 [+/−] and 4 [−/−] mice. Quantification of γ- and k-casein was done in 3 [+/+], 3 [+/−] and 3 [−/−] mice. Expression in heterozygous and α-casein deficient mice is presented as percentage of median casein gene expression in wild-type control mice [+/+] (set to 100%). Error bars represent standard deviations. For comparisons against wild-type mice in a one-way ANOVA p<0.05 is indicated by *, p<0.01 by **, and p<0.001 by ***. Exact p values are presented in table 6.
Mentions: The caseins are important for ion transport, mainly calcium and phosphate [35], [36]. Not surprisingly we therefore find that the lower casein protein levels in α-casein deficient mice are accompanied by a significantly lower concentration of calcium and phosphate in milk (reduced by around 90% compared to milk derived from wild-type animals; Fig. 5a).

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