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

描述（由申请人提供）：在美国和发达国家，肥胖症和代谢综合征X的发病率呈流行病趋势。母乳喂养对儿童和成人肥胖的发展提供了适度的保护，可能是通过围产期代谢编程机制。建议在婴儿出生后的前6个月进行纯母乳喂养，但由于母亲对婴儿饱腹感的感知以及她满足母乳需求的能力等诸多因素，目前尚未实现。乳脂是母乳的主要能量成分，对婴儿饱腹感和母乳的一些健康特性很重要。然而，乳脂浓度和脂肪酸（FA）分布是母乳中最易变化的成分。不同女性的母乳脂肪浓度不同，用膳食脂肪代替碳水化合物降低了新生合成脂肪酸的比例，而且在某些饮食中，乳脂浓度和形态遵循昼夜节律。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）抑制乳脂合成中的功能作用时，我们观察到S14缺失小鼠对这种生物活性FA有高反应。因此，我们提出S14的表达通过改变第二种脂肪生成调节途径的反应性或有效性来调节脂肪生成。基于这一观察和S14阴性小鼠在不同食物中表型的差异，我们提出了S14阴性小鼠的乳脂合成对饮食因素高度敏感的假设。我们认为这代表了一种新的营养-基因相互作用，以及S14在膳食因子调节脂质合成中的功能作用的新范式。这个

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.)