Harnessing Cells from Human Milk; Linking Lactation to Metabolism

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Project Summary: Breastfeeding has been shown to protect mothers and their children from metabolic disease later in life. However, maternal obesity and diabetes independently predict poor lactation outcomes, even after adjustments for breastfeeding support and socioeconomic factors. The physiological reasons for this relationship remain unclear. This proposal aims to identify the molecular mechanisms linking lactation to metabolism with a long-term goal of developing interventions to improve lactation outcomes in women with obesity and/or diabetes. Investigations of human lactation are challenging due to ethical and practical barriers related to accessing mammary tissue in the lactating state. Single cell RNA sequencing of human milk-derived cells has shown that these cells are remarkably similar to mammary epithelial cells (MECs) resident in the lactating gland. Additional cell sorting efforts have established milk-derived MECs as “liquid breast biopsies” which may be used to answer many outstanding questions regarding lactation biology. Furthermore, a delicate balance of insulin signaling is required for MEC differentiation and maintenance. Mammary specific knockout of the insulin receptor (mam-IRKO) blocks MEC secretory differentiation, and therefore impedes lactation. Conversely, mammary-specific expression of an active form of insulin’s downstream mediator, AKT, also drives lactation failure. In order to identify appropriate interventional approaches to improve lactation performance, it is critical to understand if MECs are responsive or resistant to insulin in the context of hyperinsulinemia. Studies of non-lactating mammary glands in women with obesity and diet-induced obese mice suggest that premature insulin signaling may be responsible for these effects, by driving dysregulated glandular development. The aims of this project are to 1. establish the effect of maternal gestational diabetes (GDM) on MEC progenitor insulin signaling and milk-derived MEC profiles and 2. define the effects of insulin and other metabolic hormones on MEC secretory differentiation and function. Milk-derived MECs of women with and without severe GDM, matching for BMI, will be utilized to determine if MEC progenitors from women with GDM are sufficiently responsive or resistant to insulin, and differences between MEC populations which may explain impaired lactation outcomes in these women will be assessed. In vivo and in vitro models of MEC development will be used to identify the mechanism underlying insulin’s effect on lactogenic prolactin signaling, which is downregulated in mam-IRKO mice. Effects of adipokines leptin and adiponectin on MEC development and function will also be investigated. This proposal will inform future efforts to investigate additional links between obesity and/or diabetes and human lactation dysfunction. The proposed approach has the potential to break a vicious intergenerational cycle of metabolic disease. A collaborative team of experts in mammary physiology and diabetes in pregnancy will support the applicant to ensure success of this innovative project.