Location: Children's Nutrition Research CenterTitle: Gene regulation of UDP-galactose synthesis and transport: Potential rate limiting processes in initiation of milk production in humans Author
Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/18/2012
Publication Date: 8/1/2012
Citation: Mohammad, M.A., Hadsell, D.L., Haymond, M.W. 2012. Gene regulation of UDP-galactose synthesis and transport: Potential rate limiting processes in initiation of milk production in humans. American Journal of Physiology - Endocrinology and Metabolism. 303(3): E365-E376. Interpretive Summary: Galactose is a specific milk sugar that is slightly structurally different than glucose. Glucose, however, is a normal sugar that circulates in the blood, constituting the majority of carbohydrate consumed by human. Obese (lactating and non-lactating) women struggle to lose weight following pregnancy. We conducted a study to test whether the consumption of a diet containing only galactose compared to only glucose as the sole sugar starch source would increase the mobilization and burning of fat in obese (lactating and non-lactating) women. On the galactose-containing diet, fat mobilization and metabolism were higher in both non-lactating and lactating women when compared to the glucose-containing diet. Milk production, energy expenditure, and carbohydrate oxidation were similar between diets. We conclude that galactose consumption as the only sugar is associated with a better mobilization and oxidation of fat and may promote body fat loss in obese subjects whether lactating or not. This may serve in the basis of future strategies to address weight loss in women.
Technical Abstract: Lactose synthesis is believed to be rate-limiting for milk production. However, understanding the molecular events controlling lactose synthesis in humans is still rudimentary. We have utilized our established model of the RNA isolated from breast milk fat globule from 7 healthy exclusively breastfeeding women from 6h to 42days following delivery to determine the temporal coordination of changes in gene expression in the carbohydrate metabolic processes emphasizing the lactose synthesis pathway in human mammary epithelial cell (MEC). We showed that milk lactose concentrations increased from 75 to 200mM from 6 to 96h. Milk progesterone concentrations fell by 65% at 24h and were undetectable by day3. Milk prolactin peaked at 36h then progressively declined afterwards. In concordance with lactose synthesis, gene expression of galactose kinase2 (GK2), UDP-glucose pyrophosphorylase2 (UGP2), and phosphoglucomutase1 (PGM1) increased 18, 10 and 3 fold between 6 and 72h, respectively. Between 6 and 96h, gene expression of UDP-Galactose transporter2 (SLC35A2) increased 3 fold, while glucose transporter1 (GLUT1) was unchanged. Gene expression of lactose synthase#3 (beta4GALT3) increased 1.7 fold by 96h, while a-lactalbumin (LALBA) did not change over the entire study duration. Gene expression of prolactin receptor (PRLR) and its downstream Signal transducer and activator of transcription complex5 (STAT5) were 10.0 and 2.5 fold increased by 72h. In summary, lactose synthesis paralleled the induction of gene expression of proteins involved in UDP-galactose synthesis and transport, suggesting that they are potential rate-limiting in lactose synthesis and, thus, milk production. Progesterone withdrawal may be the signal that triggers PRLR signaling via STAT5 which may in turn induce UGP2 and SLC35A2 expression.