The long term objectives of our research are to define the interactions between lactational performance and maternal metabolism and determine the mechanisms of these interactions. During the preceding grant period we provided evidence that the regulation of glucose metabolism and the regulation of milk volume secretion are remarkably independent. This adaptation allows milk production to continue at normal levels during a at least short periods of starvation and constitutes, therefore, a major mechanism of infant survival under nutritionally adverse circumstances. Another important component of reproductive adaptation in the human, as well as animals is the propensity to lay down substantial fat stores during pregnancy, fat stores that become available to support milk synthesis during periods of nutritional deprivation. Moreover, milk fat composition is subject to dietary regulation even in the presence of adequate nutritional resources. Our research efforts during the next project period will be directed toward elucidating the mechanisms of these adaptations, focussing on the pivotal enzyme, lipoprotein lipase (LPL). Because there are fundamental questions about the biology of LPL at the molecular, cellular and organismic level, most of our experiments will be carried out in mice, a species in which the enzyme undergoes and mammary tissue from the lactating mouse. To elucidate the mechanism or mechanisms of these effects we plan to test the following hypothesis: LPL is synthesized and secreted by mammary adipocytes and responds to both local regulatory signals from neighboring mammary alveolar cells and general metabolic signals exemplified by the fed and fasted states. (1) We will use immunocytochemical techniques and in situ hybridization to localize the site or sites of synthesis of LPL within the mouse mammary gland, specifically determining the relative roles of epithelial cells and adipocytes in this process. (2) We will determine the relation between tissue and milk LPL under a number of physiological conditions and use morphologic techniques to define the pathway for transport of LPL into milk. (3) We will develop an in vivo model for the study of the regulation of mammary LPL at the cellular and molecular level and determine the relative roles of mRNA transcription and stability, as well as protein degradation, in changes in LPL synthesis and secretion. (4) We will examine putative local interactions between mammary cells and adipocytes using coculture techniques to answer the questions: Do mammary cells stimulate LPL synthesis by adipocytes? Do mammary cells alter lipolysis in adipose tissue? 5. The role of LPL in modulating milk triglyceride secretion and composition in response to diet will be addressed in humans where the rates of LPL secretion into milk can be directly correlated to the fatty acid composition and triglyceride content of the milk under highly controlled circumstances.
| Schwertfeger, Kathryn L; McManaman, James L; Palmer, Carol A et al. (2003) Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation. J Lipid Res 44:1100-12 |
| McManaman, James L; Neville, Margaret C (2003) Mammary physiology and milk secretion. Adv Drug Deliv Rev 55:629-41 |
| Neville, M C; Morton, J; Umemura, S (2001) Lactogenesis. The transition from pregnancy to lactation. Pediatr Clin North Am 48:35-52 |
| Neville, M C (2001) Anatomy and physiology of lactation. Pediatr Clin North Am 48:13-34 |
| Neville, M C (1999) Physiology of lactation. Clin Perinatol 26:251-79, v |
| Toddywalla, V S; Kari, F W; Neville, M C (1997) Active transport of nitrofurantoin across a mouse mammary epithelial monolayer. J Pharmacol Exp Ther 280:669-76 |
| Jensen, D R; Gavigan, S; Sawicki, V et al. (1994) Regulation of lipoprotein lipase activity and mRNA in the mammary gland of the lactating mouse. Biochem J 298 ( Pt 2):321-7 |
| Neville, M C; Sawicki, V S; Hay Jr, W W (1993) Effects of fasting, elevated plasma glucose and plasma insulin concentrations on milk secretion in women. J Endocrinol 139:165-73 |
| Neville, M C; Waxman, L J; Jensen, D et al. (1991) Lipoprotein lipase in human milk: compartmentalization and effect of fasting, insulin, and glucose. J Lipid Res 32:251-7 |
| Jensen, D R; Bessesen, D H; Etienne, J et al. (1991) Distribution and source of lipoprotein lipase in mouse mammary gland. J Lipid Res 32:733-42 |
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