LACTATIONAL EFFECTORS OF TRIACYLGLYCEROL MOBILIZATION

描述（由申请方提供）：哺乳期小鼠是研究脂肪库脂质含量调节的显著模型。在典型的20天哺乳期，小鼠乳腺分泌约一个体重当量的三酰甘油进入乳汁。在这个过程中，小鼠几乎完全变瘦，断奶后恢复到哺乳前的身体组成。虽然哺乳相关的脱脂脂肪库已被公认在啮齿类动物和奶牛物种，所涉及的机制在很大程度上是未知的，脂肪库之间的差异，在他们的反应，哺乳很少受到关注。在完整的小鼠中，乳腺脂肪垫的脱脂比外周非乳腺脂肪垫的脱脂发生得更快，更完全，我们将这种现象归因于乳腺上皮和乳腺脂肪垫之间的串扰。当乳腺脂肪垫清除上皮成分时，它对导致子宫和肾周脂肪垫脱脂的全身影响几乎没有反应。由于这些脂肪垫的脱脂程度似乎与催乳素受体表达以及催乳素下游信号分子SOCS-2的表达大致成比例，因此我们假设泌乳期间高水平的循环催乳素作为全身性脂解因子。为了验证这一假设，我们将评估催乳素受体信号传导和催乳素对处女和哺乳中期小鼠各种脂肪垫的直接影响;催乳素受体也将在培养的脂肪细胞中表达。将使用基于特定细胞的定向基因阵列测定来确定催乳素对脂肪代谢的影响。为了验证上皮源性旁分泌因子负责完整乳腺脂肪垫脱脂的假设，我们将使用高分辨率蛋白质组学方法结合敏感的细胞培养测定。我们的目的是确定从培养的乳腺上皮细胞分泌的物质，增加脂肪细胞脂解活性。通过这些研究，我们希望获得有价值的洞察女性生殖激素如何影响脂肪细胞生物学以及乳腺上皮细胞如何与乳腺脂肪细胞沟通，以调节能量储存。此外，这项研究的长期结果应该导致更好地理解各种脂肪组织库在肥胖，代谢综合征和妊娠糖尿病等复杂疾病的发生中的作用。

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.