The differentiation of mammary epithelial cells into secretory cells for lactation is of great importance to survival of newborn mammals. Prolactin is critical in this process and the focus has been upon the regulation of milk protein gene transcription by prolactin. Characterizing mammary differentiation solely on the basis of the regulation of milk protein synthesis provides a one-dimensional view of this complex process. In addition to stimulating transcription of milk protein genes, prolactin provides a survival signal and may stimulate other physiologic processes including glucose transport and lipid biosynthesis. Our research with transgenic mice that express constitutively activated Akt1 in the mammary gland suggests that regulation of Akt and glucose levels in mammary epithelial cells may be necessary to 1) maintain """"""""balanced aerobic glycolysis"""""""" which leads to the proper ratio of lipid and lactose in the milk, and 2) promote survival of mammary epithelial cells. The glucose transporter GLUT1 is the predominant transporter expressed in the lactating mammary gland. We hypothesize that activation of Akt by lactogenic hormones stimulates translocation of GLUT1 to the plasma membrane and increases hexokinase activity. These changes result in an increase in the cytosolic concentrations of glucose and glucose-6-phosphate. As a consequence the increase in glucose and glucose-6-phosphate stimulates fatty acid biosynthesis due to the increased production of pyruvate and NADPH via glycolysis; and maintains mitochondrial membrane potential thus promoting cell survival. We propose to use magnetic resonance spectroscopy to determine the metabolic basis for the increased lipid biosynthesis in MMTV-myr-Akt1 transgenic mice. We hypothesize that overexpression of activated Akt should increase the pyruvate concentration in mammary cells at the expense of intracellular glucose and glucose-6-phosphate, increase citrate levels, and decrease lactose synthesis relative to lipid synthesis. In the second aim we will determine whether there is a lactation defect in Akt1 null mice. In the third aim, we will generate transgenic mice in which the expression of hexokinase-I in the mammary gland is conditionally regulated using the Tet-On system, to test the hypothesis that overexpression of hexokinase during lactation will result in a lactation failure due to an imbalance in the synthesis of lipids versus lactose. In the fourth aim we will overexpress GLUT1 to determine whether this will suppress involution of the mammary gland.
These aims address fundamental questions about the metabolic pathways regulating biosynthesis of lipids and lactose, and the role of glucose metabolism in regulating apoptosis using in vivo models.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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University of Colorado Denver
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Rudolph, Michael C; Jackman, Matthew R; Presby, David M et al. (2018) Low Neonatal Plasma n-6/n-3 PUFA Ratios Regulate Offspring Adipogenic Potential and Condition Adult Obesity Resistance. Diabetes 67:651-661
Checkley, L Allyson; Rudolph, Michael C; Wellberg, Elizabeth A et al. (2017) Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor RegressionIn Vivo. Cancer Prev Res (Phila) 10:198-207
Rudolph, M C; Young, B E; Lemas, D J et al. (2017) Early infant adipose deposition is positively associated with the n-6 to n-3 fatty acid ratio in human milk independent of maternal BMI. Int J Obes (Lond) 41:510-517
Baumgartner, Heidi K; Rudolph, Michael C; Ramanathan, Palaniappian et al. (2017) Developmental Expression of Claudins in the Mammary Gland. J Mammary Gland Biol Neoplasia 22:141-157
Heinz, Richard E; Rudolph, Michael C; Ramanathan, Palani et al. (2016) Constitutive expression of microRNA-150 in mammary epithelium suppresses secretory activation and impairs de novo lipogenesis. Development 143:4236-4248
Grimm, Sandra L; Hartig, Sean M; Edwards, Dean P (2016) Progesterone Receptor Signaling Mechanisms. J Mol Biol 428:3831-49
TreviƱo, Lindsey S; Bolt, Michael J; Grimm, Sandra L et al. (2016) Differential Regulation of Progesterone Receptor-Mediated Transcription by CDK2 and DNA-PK. Mol Endocrinol 30:158-72
Sladek, Celia D; Stevens, Wanida; Song, Zhilin et al. (2016) The ""metabolic sensor"" function of rat supraoptic oxytocin and vasopressin neurons is attenuated during lactation but not in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 310:R337-45
Libby, Andrew E; Bales, Elise; Orlicky, David J et al. (2016) Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome. J Biol Chem 291:24231-24246
Rudolph, Michael C; Young, Bridget E; Jackson, Kristina Harris et al. (2016) Human Milk Fatty Acid Composition: Comparison of Novel Dried Milk Spot Versus Standard Liquid Extraction Methods. J Mammary Gland Biol Neoplasia 21:131-138

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