A Cross Fostering Study in Mice Suggests Effects of Milk Composition on the Adult Obesity of Offspring

Inbred mouse strains have been used to identify genes that influence human obesity. A specific type of inbred mouse strain, congenic mouse strains, are used as tools to identify genes influencing many complex traits, including obesity. Congenic strains are generated by crossing two inbred strains such that a selected region of DNA from one inbred strain (donor strain) is introgressed into the genome of the other inbred strain (background strain). The congenic mouse strain has all background strain DNA, except for the selected donor region.   Differences in obesity between congenic and background strains are due to the donor strain alleles in the donor region.   We have created a lean congenic strain containing BALB/c donor strain DNA from distal chromosome 7 on the C57BL/6ByJ background strain. Our congenic donor region contains the D7Mit353 marker and spans approximately 10 Mb. This congenic strain is annotated B6.C-D7Mit353, but will be subsequently denoted as 353 in this abstract. The small region of BALB/c DNA causes the mice to be leaner than the control C57BL/6ByJ mice which lack BALB/c DNA.

We performed a cross-fostering (adoption) study between 353 and C57BL/6ByJ mice. In this study, whole litters born to 353 and C57BL/6ByJ mice on the same day were normalized to six pups who were either raised by their birth mothers or a nurse mother of the other genotype. We found that the identity of the nurse mother had post partum effects on obesity in the progeny and that these effects were carried through adulthood. Measures of adiposity index, calculated as the sum of the four main fat depot weights divided by the live fasted weight at sacrifice, differed significantly between pups of the same genotype raised by their birth mother or a nurse mother. One-way ANOVA with Bonferroni post hoc tests for maternal care effects revealed that 353 pups raised by nurse mothers had significantly greater adiposity than those raised by their birth mother (mean adiposity difference=1.749 ± 0.520; p-value=0.002). C57BL/6ByJ pups raised by a nurse mother also had significantly greater adiposity than those raised by their birth mother (mean adiposity difference=2.508 ± 0.533; p-value=0.000). From this data, we conclude that some aspect of maternal care, most likely nursing, changes offspring adult adiposity. Interestingly, this effect appears to outweigh direct genetic effects for the determination of adiposity in our experimental system.

Our current hypothesis to explain these findings is that differences in milk composition or abundance between C57BL/6ByJ and 353 mothers are the causative factor in our observed significant effect of post partum maternal care on adulthood obesity. In previous work, we have shown that 353 mice differ from C57BL/6ByJ mice for expression of a prohormone protease, prolyl carboxypeptidase, that influences obesity and may influence the hormonal composition of milk. We are currently preparing to assay milk constituents, including bioactive hormones, that may account for our observed obesity effects.  Once the milk bioactive influencing obesity is identified in mice, then its presence and regulation can be measured in commercially important species and in humans.