ABSTRACT
Maternal metabolism during pregnancy is a key contributor to developmental origins of metabolic disease.
Offspring exposed to maternal hyperglycemia and obesity have increased rates of obesity and disordered
glucose metabolism. The lactation period is also a critical window for programming. Lactogenesis initiates in
the second half of gestation, thus human milk (HM) biosynthesis is susceptible maternal metabolism.
Interindividual variation in HM nutrients reveals the influence of maternal metabolism on milk biosynthesis. A
knowledge gap exists as to whether HM composition alters developmental pathways of offspring programmed
in utero. Maternal metabolic states including gestational diabietes (GDM) and obesity alter HM nutrient profiles,
including milk fatty acids (FA). Our studies identified altered HM linoleic acid and dihomo-gamma-linolenic acid
(DGLA) in conditions of maternal diabetes, hyperglycemia, and obesity, as well as HM palmitic acid and DGLA
associations with infant growth. However, any impact of maternal metabolism across the entire range of
glycemia on both HM composition and offspring programming has not been evaluated in context of detailed
profiling of in utero exposures. Our goal is to understand how HM susceptibility to maternal metabolism
impacts offspring metabolism, identifying interventions to mitigate adverse developmental programming. This
proposal’s objective is to determine the impact of maternal glycemia in pregnancy on HM composition and
effects of HM nutrients on offspring adiposity. Translational science approaches will determine how maternal
glycemia alters mammary gland epithelial cell gene expression and how HM lipids across the range of
maternal glycemia regulate infant adipoctyes. Our overarching hypothesis is that maternal glycemia in normal
and pathologic ranges impacts HM composition, which in turn influences offspring metabolic programming as
reflected by early childhood adiposity. Capitalizing on the detailed metabolic phenotyping of the GO MOMs
cohort, we will conduct prospective HM profiling at 1, 2 and 6 months post-partum in a cohort of 450 women to
associate maternal glycemia during and after pregnancy, focusing on HM lipids known to regulate offspring
adiposity (Aim 1). Mammary epithelial cells shed in expressed HM will be evaluated using transcriptomics
(SubAim 1). For reproducibility, HM lipids will be compared to a separate validation cohort enrolling women
with GDM. We will measure offspring body composition to discern adiposity at months 1, 2, and 6 and 2 years,
accounting for childhood diet (Aim 2). A human infant preadipocyte strain will be exposed to HM lipids collected
and grouped by quartiles of maternal glycemia to determine mechanisms altering infant adipocyte development
(Aim 3). Completing the aims will define HM composition in a pregnancy cohort with comprehensive metabolic
profiling throughout pregnancy and lactation across the range of glycemia and BMI. Offspring growth and
translational studies will advance understanding of how lactation exposures modify in utero programming. This
will further the field by revealing interventions to reduce risk of adverse offspring metabolic health.
