Location: Children's Nutrition Research Center
2023 Annual Report
Objectives
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.
Progress Report
We had previously completed a study that shows a connection between a specific protein in fat cells, named Connexin43, and the amount of lactose in breast milk. If this protein is missing, the breast milk has less lactose. As a result, baby animals fed this milk do not gain as much weight. This indicates that the way fat cells communicate with each other plays a big role in breast milk production.
This year, we have completed collecting metabolic data of offspring outlined in Objective 2. In summary, baby mice from the mother lacking Connexin43 in their adipocytes were lighter in weight when they were very young. But by the time they were eight weeks old, they weighed the same as those fed by normal mothers. If they ate a fatty diet from that age, they gained more weight than the others, especially in terms of fat tissue. They also had issues processing sugar when they hadn't eaten overnight but responded to insulin similarly. This suggests that babies fed by mothers missing the Connexin43 protein may have more risks related to sugar metabolism later in life.
An additional project was initiated last year. During breast feeding, female mammals eat a lot more food, which is associated with higher levels of the hormone prolactin and lower effect of estrogen, compared to those not lactating. We aim to determine whether this low estrogen effect causes the high feeding and prolactin level during lactation, and our experiments are ongoing as planned.
During FY 2023 for Objective 3, we conducted two experiments to distinguish the effect of estrogen between peripheral organs and the brain. We supplemented estrogen to lactating mice through circulation or directly to the brain, respectively. Our results support the conclusion that central estrogen can reduce prolactin level without reducing feeding of lactating dams and/or survival of pups. This could be due to reduced estrogen responsiveness that even additional more estrogen cannot trigger bigger effect. We will further confirm these results with another cohort of mice.
In Objective 4, we used a strategy to mimic brain estrogen effect by artificially activating a population of neurons that express estrogen receptor alpha in lactating mice. We generated a cohort of mice and results showed that activation of these neurons reduced prolactin levels and food intake of lactating mice. These results support that suppressed estrogen signaling is required to maintain high prolactin levels and high feeding in breast feeding mothers. We will further confirm these results with a larger cohort of mice.
In Objective 5 we generated a cohort of mice with supplement of estrogen to the brain and meanwhile artificially inhibit this population of neurons in lactating mice. We have collected all of the samples and will further analyze the samples and reach a conclusion.
Accomplishments
1. A novel role of estrogen in inhibiting prolactin production. It is well known that estrogen can directly promote prolactin production which is important for female health. However, the indirect impacts of estrogen are not well studied. Researchers at the Children's Nutrition Research Center in Houston, Texas, discovered that estrogen can inhibit prolactin levels indirectly during lactation through the brain, which may contribute to the remodeling of the energy balance in mothers. Additional studies are necessary to fully explore the detailed mechanism for brain estrogen effect on prolactin and study the impact of this mechanism on maternal health.
