Nearly one in four women begins pregnancy when they are obese in the year of 2011. Obesity not only puts the mother at high risk of a number of pregnancy complications, but also put the baby at higher risk of birth defects and metabolic complications. In the non-lactating mammary gland, adipocytes comprise a large proportion of the stroma. Intriguingly, mammary adipocytes dramatically regress during pregnancy and rapidly regenerate after weaning. Obesity causes mammary adipose tissue inflammation and incomplete regression, which co-occurs with insufficient breastfeeding Understanding how mammary adipocytes normally remodels is essential for unmasking how obesity induced dysfunction of adipose tissue impairs mammary gland function. This remodeling is also an excellent physiological model to study adipose tissue plasticity: knowing the natural mechanism(s) that effectively regulate mammary adipose tissue mass can be used to find better strategies against obesity. Utilizing the inducible, adipocyte-specific lineage tracing AdipoChaser mouse model I generated previously, we are in a unique position to study this remodeling in an in vivo setting. My new preliminary data in AdipoChaser mice shows that the mammary adipocytes lose lipid droplets and stay close to the alveolar structures during pregnancy and lactation. More interestingly, these quiescent, lipid-free cells give rise to the mammary adipocytes regenerated during mammary involution. My central hypothesis is: during pregnancy, a certain pool of the mammary adipocytes dedifferentiates back to adipocyte precursor-like cells; only these dedifferentiated mammary adipocytes will proliferate and redifferentiate back into mature adipocytes after weaning. This hypothesis will be tested in two Specific Aims in this two-year period R03 funding, yielding novel mechanistic insights into how mammary adipocyte plasticity occurs.
In AIM 1, we will determine how mammary adipocytes dramatically remodel during female reproduction, by pulse-chasing mammary adipocytes and co-label them with proliferation and apoptosis markers during reproduction in AdipoChaser mice. We will also trace the contribution of adipocyte precursor cells to the regenerated mammary adipose tissue by using adipocyte precursor-specific pulse-chase lineage tracing MuralChaser mouse model.
In AIM 2, we will identify the regulatory mechanisms of mammary adipocyte dedifferentiation during pregnancy. We will classify how far have these dedifferentiated adipocytes gone back towards stem cell, and also use RNA-seq technology to identify the specifically altered transcriptional programs during the dedifferentiation. The studies proposed herein will build upon these original observations and unique mouse models to unmask a remarkable plasticity of the mature adipocyte, which will change the general understanding of adipocyte flexibility. We will also offer novel molecular targets for controlling adipose tissue mass, in order to treat obesity and its negative physiological sequelae.
Adipocytes in the female mammary gland dramatically regress during pregnancy and rapidly regenerate after weaning, offering an excellent physiological model for studying adipose tissue plasticity. The proposed experiments in this proposal will determine how mammary adipocytes dramatically remodel during female reproduction. This knowledge will facilitate our attempts to manipulate fat tissue mass as a therapeutic treatment for obesity and its related metabolic disorders.