Metabolic regulation in the lactating mammary gland: a lipid synthesizing machine

Abstract

The mammary gland of the lactating mouse synthesizes and secretes milk lipid equivalent to its entire body weight in a single 20-day lactation cycle, making it one of the most active lipid synthetic organs known. We test the hypothesis that multiple control points and potential regulatory mechanisms regulate milk lipid synthesis at the level of gene expression. The mammary transcriptome of 130 genes involved in glucose metabolism was examined at late pregnancy and early lactation, utilizing data obtained from microarray analysis of mammary glands from quadruplicate FVB mice at pregnancy day 17 and lactation day 2. To correlate changes with physiological parameters, the metabolome obtained from magnetic resonance spectroscopy of flash-frozen glands at day 17 of pregnancy was compared with that at day 2 of lactation. A significant increase in carbohydrates (glucose, lactose, sialic acid) and amino acids (alanine, aspartate, arginine, glutamate) with a moderate increase in important osmolytes (myoinositol, betaine, choline derivatives) were observed in the lactating gland. In addition, diets containing 8% or 40% lipid were fed from lactation days 5-10 and mammary glands and livers of triplicate FVB mice prepared for microarray analysis. The results show that substantial regulation of lipid synthesis occurs at the level of mRNA expression and that some of the regulation points differ substantially from the liver. They also implicate the transcription factor SREBP-1c in regulation of part of the pathway. lipid synthesis; microarray; metabolomics; dietary lipid; magnetic resonance spectroscopy THE MOUSE MAMMARY GLAND OFFERS an outstanding model system for examining developmental regulation of metabolic processes. Pregnancy in this species lasts ϳ19 days including an intensive proliferative phase followed by a differentiation phase marked by an increase in milk protein gene expression, lipid droplet formation, and stromal adaptations (42,43). A fall in progesterone ϳday 18 initiates secretory activation, a programmed series of changes in the epithelium that leads to the copious secretion of very rich milk consisting of ϳ12% protein, 30% lipid, and 5% lactose. Lipid synthesis is particularly remarkable: The mammary gland of the FVB mouse must synthesize an amount of triacylglycerol (TAG) equivalent to the entire weight of the mouse during a 20-day lactation, generally while the mouse is eating a diet containing Ͻ8% of the calories as fat (37).Coordinate transcriptional regulation of many of the lipid synthesis enzymes occurs in other organs such as the liver (12, 17) and adipose tissue (39) as well as pancreatic ␤-cells (2). We hypothesized that coordinate regulation of the same pathways might be integral to the remarkable increase in lipid and lactose synthesis during the activation of secretion (sometimes called lactogenesis II) in the mammary gland. We wished to identify both the key enzymes that change during the initiation of this program and the transcriptional regulators involved.Our strategy was first to utilize...

Lipid-deprived diet perturbs O-glycosylation of secretory proteins in rat mammary epithelial cells

“…Indeed, if this is true for MECs, it would be compatible with higher lactose in the milk of lipid-deprived rats. Supporting this, it has recently been shown that expression of both hexokinase and glucose phosphate isomerase is downregulated in mouse at the initiation of lactation (Rudolph et al, 2007). This would favour the partitioning of glucose towards lactose production by decreasing its consumption for glycolysis, in the pentose phosphate cycle and the hexosamine biosynthetic pathways.…”

Inhibition of FASN reduces the synthesis of medium-chain fatty acids in goat mammary gland

“…Our previous study has shown a significant inhibition on ACCα expression by PPARγ knockdown . It is generally believed that SREPB1 plays a key role in regulation of mammary lipogenesis including mice (Rudolph et al, 2007), sheep (Hussein et al, 2013) and dairy cows (Harvatine et al, 2009). In general, the expression of SREBP1 is decreased to even a greater extent than the expression of several lipogenic genes, including the ones measured above, along with those associated with triglyceride assembly and desaturation (Harvatine et al, 2009).…”

Milk Protein Synthesis in the Lactating Mammary Gland: Insights from Transcriptomics Analyses

“…In Figure 1 are reported the temporal patterns of transcription of caseins, alpha-lactalbumin, whey acid protein, and albumin from pregnancy to lactation in two ruminant species (dairy cow [89] and dairy goat [90]), two monogastric species (mouse [91] and pig [92]), and a marsupial (kangaroo; Macropus eugenii [93]). Those were the only microarray datasets publicly available at the time of this writing.…”