LACTATIONAL EFFECTORS OF TRIACYLGLYCEROL MOBILIZATION

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DESCRIPTION (provided by applicant): The lactating mouse presents a remarkable model for the study of the regulation of the lipid content of adipose depots. During typical 20-day lactation the murine mammary gland secretes approximately one body weight equivalent of triacylglycerol into the milk. During this process the mouse becomes almost entirely lean, returning to its pre-lactation body composition after weaning. Although lactation related delipidation of adipose depots has long been recognized in both rodents and dairy species, the mechanisms involved are largely unknown and the differences between adipose depots in their response to lactation have received little attention. In the intact mouse, delipidation of the mammary fat pads occurs faster and more completely than does delipidation of the peripheral, non-mammary fat pads, a phenomenon we ascribe to cross-talk between the mammary epithelium and the mammary fat pad. When the mammary fat pad is cleared of epithelial elements, it becomes almost unresponsive to the systemic influences that lead to delipidation of the uterine and perirenal fat pads. Because the degree of delipidation in these fat pads appears to be roughly proportional to prolactin receptor expression as well as to expression of a prolactin downstream signaling molecule, SOCS-2, we hypothesize that the high level of circulating prolactin during lactation acts as the systemic lipolytic factor. To test this hypothesis, we will assess prolactin receptor signaling and direct effects of prolactin on various fat pads of virgin and mid-lactating mice; the prolactin receptor will also be expressed in cultured adipocytes. Specific cell based and directed gene array assays will be used to define prolactin effects on adipose metabolism. To test the hypothesis that an epithelial- derived paracrine factor is responsible for the delipidation of the intact mammary fat pad, we will use high- resolution proteomic approaches in conjunction with sensitive cell culture assays. We aim to identify substances secreted from cultured mammary epithelial cells that increase adipocyte lipolytic activity. Through these studies, we hope to gain valuable insight into how female reproductive hormones influence adipocyte biology as well as how the mammary epithelial compartment communicates with the mammary adipose compartment to regulate energy stores. In addition, the long term ramifications of this study should lead to better understanding the role of various adipose tissue depots in the genesis of such complex disorders as obesity, metabolic syndrome, and gestational diabetes.