Functional role of the Spot 14 gene in dietary regulation of milk fat synthesis

描述(申请人提供)：在美国和发达国家，肥胖症和代谢综合征X的发病率呈上升趋势。母乳喂养对儿童和成人肥胖的发展提供适度的保护，可能是通过围产期代谢编程机制。建议在婴儿出生后6个月内进行纯母乳喂养，但目前还不能完全母乳喂养，原因包括母亲S对婴儿S饱腹感的看法，以及她满足母乳需求的能力。乳脂是母乳的主要能量成分，对婴儿的饱腹感和一些已被证明的母乳的健康特性非常重要。然而，乳脂浓度和脂肪酸(FA)谱是母乳中变化最大的成分。不同女性母乳脂肪含量不同，以膳食脂肪代替碳水化合物可降低乳汁中从头合成脂肪酸的比例，在某些饮食中，乳脂浓度和乳脂含量呈昼夜节律变化。在研究甲状腺激素反应点14(S14)在反式-10，顺式-12共轭亚油酸(CLA)抑制乳脂合成中的作用时，我们观察到S14缺失的小鼠对这种生物活性FA具有高反应性。因此，我们认为S14的表达通过改变第二个生脂调节途径的响应性或有效性而在脂肪形成的调节中起重要作用。基于这一观察结果和S14基因缺失小鼠在不同饮食中的表型差异，我们提出了S14基因缺失小鼠的乳脂合成对饮食因素高度敏感的假说。我们认为这代表了一种新的营养-基因相互作用和S14在饮食因素调节脂质合成中的功能作用的新范例。这个 拟议的工作将测试饮食因素对已建立的哺乳期间乳脂代谢的影响。具体地说，我们将研究S14在乳脂对膳食脂肪浓度和FA含量、一天中的时间和短期饲料限制的反应中的作用。主要的反应变量包括幼崽生长、母猪饲料摄入量和幼崽乳脂含量。最后，我们将通过检测关键的脂肪生成酶和转录因子的mRNA和蛋白质表达来表征最有效的饮食治疗的机制。这项拟议的工作将确定S14在乳脂对饮食因素的反应中的功能作用，并对制定母乳喂养妇女饮食脂肪含量和进餐时机的建议具有重要意义。该项目还有望为S14在代谢调节中的作用提供新的见解。) 与公众健康相关：母乳喂养对肥胖的发生有适度的保护作用，但母乳脂肪因个体而异，并受饮食和一天中的时间的影响。确定调节乳脂合成的机制将为制定改善母乳健康的饮食建议提供关键的见解。)

DESCRIPTION (provided by applicant): The incidence of obesity and metabolic syndrome X are increasing towards epidemic proportions in the US and developed world. Breastfeeding provides modest protection towards development of childhood and adult obesity presumably through a perinatal metabolic programming mechanism. Exclusive breastfeeding is recommended for the first 6 months of life, but is not currently achieved because of a number of factors including mother<s perception of her infant<s satiety and her ability to meet milk demand. Milk fat is the major energy component of breast milk and is important to infant satiety and some of the documented healthful properties of breast milk. However, milk fat concentration and fatty acid (FA) profile are the most variable components of breast milk. Breast milk fat concentration is different between women, the proportion of de novo synthesized FA is decreased by substitution of dietary fat for carbohydrate, and milk fat concentration and profile follows a circadian rhythm on some diets. While investigating the functional role of Thyroid Hormone Responsive Spot 14 (S14) in trans-10, cis-12 conjugated linoleic acid (CLA) inhibition of milk fat synthesis we observed that the S14 null mouse was hyper-responsive to this bioactive FA. Thus, we proposed that S14 expression is important to regulation of lipogenesis by modifying the responsiveness or effectiveness of a second lipogenic regulatory pathway. Based on this observation and differences in the phenotype of the S14 null mouse on different chow diets we propose the hypothesis that milk fat synthesis in the S14 null mouse is hyper-responsive to dietary factors. We believe this represents a novel nutrient-gene interaction and a new paradigm of the functional role of S14 in regulation of lipid synthesis by dietary factors. The proposed work will test the effect of dietary factors on mammary lipid metabolism during established lactation. Specifically, we will investigate the role of S14 in milk fat response to dietary fat concentration and FA profile, time of day, and short-term feed restriction. Main response variables include pup growth, dam feed intake, and pup milk fat profile. Lastly, we will characterize the mechanism of the most responsive dietary treatments by determining mRNA and protein expression of key lipogenic enzymes and transcription factors. The proposed work will determine the functional role of S14 in milk fat response to dietary factors and has significant implications in development of recommendations on dietary fat content and meal timing in breast feeding women. The project is also expected to yield new insight into the role of S14 in metabolic regulation. ) PUBLIC HEALTH RELEVANCE: Breast-feeding is modesty protective in development of obesity, but breast milk fat is variable between individuals and is modified by diet and time of day. Determining the mechanisms regulating milk fat synthesis will provide key insight into developing dietary recommendations that improve the healthfulness of breast milk.)