Mammary Adipocyte Remodeling in Health and Disease

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Breastfeeding reduces the mother’s risk of type 2 diabetes and protects the child from obesity, type 2 diabetes, and other metabolic disorders. Unfortunately, mothers with obesity and type 2 diabetes often have insufficient milk production. Lactation by the breast tissue is accomplished through a serious of complicated cellular remodeling, and a “reverse” remodeling post-weaning takes place to return the breast tissue to the non-lactating state (involution). Our understanding of how breast tissue remodels during and post-weaning is limited, which impedes our ability to address lactation complications. The human breast (mammary gland) is comprised of glandular, ductal, connective, and adipose tissue; in the non-lactating mammary gland, the majority of the mass is made up of adipose tissue. My lab recently showed that during lactation, mammary adipocytes undergo a process of dedifferentiation to become adipocyte precursor-like cells; during involution, these dedifferentiated cells can proliferate, and re-differentiate back into adipocytes. Thus, for the first time, we discovered that terminally differentiated mature adipocytes can dedifferentiate, go back to cell cycle, and regain the capacity of self-renewal. Our objective for this proposal is to determine what regulate mammary adipocytes dedifferentiation during lactation, and to define the role of mammary adipocyte dedifferentiation and regeneration during lactation and involution. Our new preliminary data indicate that mammary adipocytes dedifferentiation is due to paracrine stimulation, and Wnt signaling is the top candidate that regulate this process. We also showed that short-term high fat diet feeding leads to incomplete mammary adipocyte dedifferentiation and smaller mammary alveolar structure. Furthermore, inhibiting the regeneration of mammary adipocytes leads to severely delayed mammary gland involution, persistent alveologenesis, periductal fibrosis, and milk retention. We hypothesize that mammary adipocyte dedifferentiation is regulated by paracrine factors from the mammary epithelial cells, especially Wnt signaling, and successful mammary adipocyte dedifferentiation and regeneration are essential for mammary lactation and involution. We will test our hypothesis in three specific aims. In Aim 1, we will determine the mechanisms that regulate adipocyte dedifferentiation during lactation, focusing on Wnt signaling, as well as identifying new paracrine factors. In Aim 2, we will define the role of mammary adipocyte dedifferentiation in mammary alveologenesis and lactogenesis. Specifically, we will determine if incomplete adipocyte dedifferentiation is directly correlated with impaired mammary alveologenesis and lactogenesis. In Aim 3, we will define the role of mammary adipocyte regeneration in mammary gland involution. Our findings will provide fundamental knowledge to the fields of both adipose and mammary gland biology. We will also provide novel insights into lactation and involution complications in women with metabolic disorders. Moreover, the underlying mechanism of mature adipocyte dedifferentiation will bring new strategies for the treatment of obesity.