Background

Little is known about how nutrient sensing in mammary glands affects lactation or about the interplay between mammary adipocytes and mammary epithelial cells during lactation.The mechanistic target of rapamycin(mTORC1) is a central nutrient sensor in most tissues and regulates lipid metabolism in adipocytes.Our experiments in WT mice showed that mTORC1 activity,assessed by phosphorylated S6,is increased in whole mammary glands throughout lactation compared to non-lactating females,indicating an important role for mTORC1 in milk production.To understand the effect of adipocyte mTORC1 hyperactivation on mammary gland function and offspring outcomes,we used an adipocyte mTORC1 gain of function mouse model by ablating its negative regulator Tsc1.

Methods

Knockout(KO) and wild type(WT) dams were bred at age 6-8 weeks with WT and KO age-matched males.We collected data on litter size, pup survival rate, pup weight at postnatal days(PND) 7,14,and 21,and dam milk volume production at PND10 for six litters per dam.After delivering the sixth litter,we collected milk at PND16 then immediately sacrificed the dam and extracted thoracic,abdominal and inguinal mammary glands for histology and molecular studies.Milk composition was analyzed using milk gels and creamatocrit measurement.Milk output was measured using the weigh-suckle-weigh technique.

Results

Milk collected from dams with mTORC1 hyperactivation showed around a two-fold increase in α casein and whey acidic protein levels and a 1.7-fold increase in fat percentage compared to WT dams.Dams with adipocyte mTORC1 activation trended towards having lower pup survival rate,lower average litter size,heavier pups at PND7,14,and 21,and increased milk production.

Conclusions

mTORC1 hyperactivation in mammary gland adipocytes demonstrates a novel role of this nutrient-sensing pathway in milk production and in regulation of lactation.These data could help lead to a better understanding of the regulation of milk production and its effects on offspring health.