Location: Children's Nutrition Research Center
Project Number: 3092-10700-067-040-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 8, 2020
End Date: Mar 31, 2024
Objective:
Objective 1. In wild-type animals and transgenic animals lacking a functional Connexin43 gap junction within the adipocyte, characterize the effects of Connexin43 deletion on (1) the quantity of the milk a dam produces; (2) the composition of the milk, especially the lipid composition; and (3) other non-nutritional components in the milk.
Objective 2. Characterize the effects of a dam's adipocyte Connexin43 gap junction ablation on her offspring's body weight, adipose tissue mass, and late-life responses to metabolic challenges such as overnutrition.
Objective 3: Determine whether central supplement of E2 will attenuates lactational hyperphagia and hyperprolactinemia.
Objective 4: Determine whether activation of ERalphavlVMH neurons attenuates lactational hyperphagia and hyperprolactinemia.
Objective 5: Determine whether inhibition of ERalphavlVMH neurons rescues the reduced lactational hyperphagia and hyperprolactinemia by central supplement of E2.
Objective 6: Determine which ERalphavlVMH circuit is inhibited during lactation.
Approach:
Adipocytes, the primary cell type in the non-lactating breast, display a drastic morphological change during the lactation in rodent studies: lipid-filled cells undergo lipolysis to provide fatty acids for triglyceride synthesis and also as an energy source to support milk production; they come back as lipid-laden cells once the animal is done lactating. Our objective is to assess whether breast-milk composition can be regulated by maternal adipose tissue physiology – more specifically, adipose tissue gap junction. The results of this research can be leveraged to improve milk quantity and quality to benefit infant growth and future metabolic status. The central hypothesis is that adipose tissue responds to metabolic and hormonal cues to support milk production and that the Connexin43 gap junction is required to facilitate this process by coupling a group of adipocytes together. Genetic manipulation of adipose tissue Connexin43 will be used to determine the effects of Connexin43 deletion on milk production and milk composition as well as on the offspring's metabolic health.
Additionally, researchers will develop mouse models to specifically activate or inhibit ERavlVMH neurons during lactation. We will measure serum PRL levels in lactating dams and monitor the metabolic status of lactating dams and their pups, including daily body weight and food intake of the dams, as well as the survival and body weight of pups. Further, we will also map the ERavlVMH originated neuron circuits and compare their neuron activities between virgin and lactating female mice. Accomplishment of the studies will identify a novel neuroendocrine mechanism underlying hyperprolactinemia and hyperphagia during lactation, which should have significant impact on both the postpartum metabolic health of breastfeeding moms and the nutrition supply for infants.
