Using Genomics and Mutant Mice to Dissect the Regulation of Lipid Synthesis in the Mammary Gland of the Lactating Mouse

The mammary gland of the lactating mouse is one of the most robust lipid synthetic machines known—synthesizing milk fat equivalent to the body weight of the mouse during a single lactation.  The purpose of this study is to determine the mechanisms by which this synthetic activity turns on at the onset of lactation.  Use of microarray to analyze changes in gene expression at this time as well as differences between the liver and mammary gland of the lactating mouse show that regulation occurs at several metabolic control points including
1.    Substrate transport into the mammary alveolar cell
2.    Down regulation of the glycolytic pathway
3.    Up-regulation of the pentose phosphate shunt
4.    Up-regulation of glycerol-PO4 synthesis
5.    Up-regulation of mitochondrial citrate synthesis and export
6.    Up-regulation of fatty acid and cholesterol synthesis from acetyl-CoA
From further analysis of the same data set, we hypothesize that SREBP-1c, AKT1, PRLR, C/EBPbeta are major metabolic regulators.   To test the hypothesis that SREBP-1c is important we examined lactation in the SREBP-1c knock-out mouse and found that only in the presence of low fat diets is pup growth slightly slower.  To determine whether SREBP-1a and SREBP-2 are compensating for this slow growth, we studied mice in which the SREBP export protein, SCAP, was floxed, mating this mouse with mice expressing BLG-Cre in the mammary gland.  In the absence of SCAP, pups grew very slowly; however, growth could, at least in part, be rescued by a high fat, high cholesterol diet.  These data suggest that at least part of the increase in expression of lipid and cholesterol genes at the onset of lactation is due to the high substrate demand of lipid synthesis in the face of the very low fat diet provided by chow.  Supported by NIH grant PO1- HD38129.

Margaret C. Neville and Michel C. Rudolph, University of Colorado School of Medicine, Departments of Physiology and Biophysics and OB/GYN, Aurora, CO  80045.