Location: Children's Nutrition Research Center
Project Number: 3092-10700-067-001-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2024
End Date: Mar 31, 2029
Objective:
Objective 1: Determine the role of estrogen receptor a (ERa) in the hypothalamic control of lactation-mediated alterations of thermogenesis in brown adipose tissue and metabolic adaptions.
Objective 2: Determine the acute impact of lactation on the maternal hepatic and intestine metabolome and liver-gut signaling axis.
Objective 3: Determine the long-term metabolic effect of lactation on susceptibility to metabolic syndrome.
Objective 4: Utilize species - conserved and species-unique regulatory network models for predicting the extent to which select variant-gene and gene-gene pairs interact within the mammary cell to determine lactation outcomes.
Objective 5: Utilize cell culture model(s) to screen QTL variants and genes for effects on biological functions related to lactation.
Approach:
Despite the well-known benefits of lactation for both the mother and offspring, there is a paucity of metabolomic data in lactating dams. Metabolic adaptation in the dam is coordinated by central (brain) and peripheral (such as, liver) driven mechanisms that include changes in maternal feeding patterns (hyperphagia), redirection of energy mobilization to facilitate milk production, and cholesterol and glucose metabolism. The cellular mechanisms driving these processes are known to be regulated transcriptionally, and mutations in these genes contribute to a variety of metabolic disorders. It is known that metabolic gene networks are regulated by inter-individual variation within the DNA sequence of the maternal genome, and functional studies are needed to determine the impact of these changes on maternal metabolic adaptation to lactation. To address these knowledge gaps, we will use genetically modified mouse models and comparative genetics to determine the impact of central and peripherally regulated metabolism in dams at various stages of lactation. These studies will identify novel neuroendocrine mechanisms that impact maternal feeding behaviors and energy utilization, cholesterol metabolism and glucose homeostasis, long-term metabolic adaptation, and genetic mechanisms that are essential for lactation. These findings will provide therapeutic and diagnostic targets that improve lactation outcomes and sex specific mechanisms for protection of mothers against metabolic diseases.
