LACTATIONAL EFFECTORS OF TRIACYLGLYCEROL MOBILIZATION

三酰甘油动员的泌乳效应

• 批准号: 7211182
• 负责人: James Lewis McManaman
• 金额: $ 22.45万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211182
• 关键词: Adipocytes; Adipose tissue; Attention; Biochemical; Biological Assay; Body Composition; Body Weight; Body fat; Cardiovascular Diseases; Cell Line; Cells; Complex; Complications of Diabetes Mellitus; Conditioned Culture Media; Cultured Cells; Deposition; Desire for food; Disease; Elements; Epithelial; Epithelial Cells; Epithelium; Fatty acid glycerol esters; Female; Fertility; Fractionation; Genes; Gestational Diabetes; Gland; Hormonal; Hormones; Human; Lactation; Lead; Lipids; Literature; Mammary Gland Parenchyma; Mammary gland; Mass Spectrum Analysis; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Milk; Mus; Obesity; Peripheral; Play; Pregnancy; Process; Prolactin; Prolactin Receptor; Property; Proteomics; Rattus; Receptor Signaling; Regulation; Resistance; Resolution; Risk Factors; Rodent; Role; Signal Transduction; Signaling Molecule; Study models; System; Testing; Transgenic Mice; Triglycerides; Weaning; Work; adipocyte biology; base; day; design; human disease; in vivo; insight; insulin sensitivity; lipid metabolism; lipoprotein lipase; male; mammary epithelium; paracrine; receptor expression; reproductive hormone; research study; response

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.

描述（由申请人提供）：哺乳小鼠为研究脂肪仓库脂质含量的调节提供了一个显着的模型。在典型的20天哺乳期间，鼠乳腺分泌大约一个体重，相当于三酰甘油的体重。在此过程中，小鼠几乎完全倾斜，断奶后返回其前脱位的身体成分。尽管长期以来在啮齿动物和乳制品中都认识到脂肪仓库的泌乳相关删除，但所涉及的机制在很大程度上是未知的，脂肪仓库对泌乳的反应中的差异很少受到关注。在完整的小鼠中，乳腺脂肪垫的删除速度比周围，非乳腺脂肪垫的删除更快，更全面，这是我们归因于乳腺上皮和乳腺脂肪垫之间的交叉言论的现象。当清除上皮元素的乳腺脂肪垫时，它几乎对导致子宫和周围脂肪垫脱杀的系统影响几乎没有反应。由于这些脂肪垫中的删除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的表达大致成正比，因此我们假设在泌乳过程中循环催乳素的高水平作为系统性脂质溶解因子。为了检验这一假设，我们将评估催乳素受体信号传导和催乳素对各种脂肪垫对处女和中间小鼠的直接作用；催乳素受体也将在培养的脂肪细胞中表达。特定基于细胞的基因阵列分析将用于定义催乳素对脂肪代谢的影响。为了检验上皮衍生的旁分泌因子是导致完整乳腺脂肪垫删除的假设，我们将使用高分辨率蛋白质组学方法与敏感细胞培养分析结合使用。我们的目的是确定从培养的乳腺上皮细胞中分泌的物质，这些细胞增加脂肪细胞脂溶作用。通过这些研究，我们希望对女性生殖激素如何影响脂肪细胞生物学以及乳腺上皮室如何与乳腺脂肪室进行调节能量储存的方式有宝贵的见解。此外，这项研究的长期影响应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起源中的作用。