Impact of maternal vitamin D deficiency on body composition: the role of muscle and fat development

这项研究提案的总体目标是确定母体维生素D状况在早期发育过程中对后代整个生命周期健康影响的重要性。维生素D是一种微量营养素，在骨骼系统的生长和维持以及钙稳态的调节中具有公认的作用，许多研究将低血液25（OH）D浓度与肌肉骨骼功能（包括佝偻病、骨软化症、骨质减少、骨质疏松症和骨折发生率增加。然而，维生素D受体（VDR）在几种组织中表达，表明其具有广泛的生物学功能。研究人员发现，维生素D状态可能与其他疾病有关，包括肥胖，胰岛素抵抗，心血管疾病和代谢综合征。低日照、膳食维生素D摄入量减少和年龄较大是与维生素D缺乏症（VDD）相关的最常见因素，全球VDD的患病率约为10亿，女性的不足率高于男性。在英国，67%的孕妇/哺乳期妇女缺乏维生素D，这是令人担忧的，因为有证据表明维生素D可能对孕产妇健康和正常胎儿和/或产后发育至关重要。胎儿维生素D浓度主要取决于母体水平，越来越多的证据表明，发育期间维生素D的次优水平可能通过对肌肉和脂肪组织的影响对健康产生负面影响。怀孕期间维生素D不足与先兆子痫、妊娠期糖尿病和母亲剖腹产的风险增加有关，而许多研究表明，婴儿出生体重低，胎龄小，骨骼生长减少，骨骼矿化不良，骨矿物质含量较低，到6岁时脂肪量较大。而体内研究表明，在发育期间暴露于VDD环境的小鼠的前脂肪细胞中的增殖和脂滴显著增加。肌肉内脂质沉积的增加与肌肉性能的功能限制以及导致肌肉功能下降的肌肉组织炎症和萎缩的增加有关。此外，骨骼肌中的脂质积聚是胰岛素抵抗和糖尿病发展的重要危险因素。这种脂肪的起源和细胞定位尚不清楚，但一种可能性是，它是在肌肉中存在的肌源性前体细胞转分化成成熟脂肪细胞时形成的，正如我们以前的研究所表明的那样。低生理浓度（维生素D缺乏状态）导致C2C12细胞（一种肌肉细胞系）中脂滴形成增加，脂肪形成标志物增加。因此，我们提出，在发育过程中缺乏维生素D可能有利于脂肪形成，而代价是肌肉发育。因此，结合体外和体内方法，本项目的目的是确定怀孕期间缺乏维生素D是否会影响胎儿骨骼肌和脂肪组织发育所涉及的细胞过程，以及这些过程是否会随后影响所产生后代的能量消耗和整体身体组成。

The overall aim of the research proposal is to determine the importance of maternal vitamin D status during early development on health implications across the lifespan of offspring.Vitamin D is a micronutrient with a well established role in growth and maintenance of the skeletal system and regulation of calcium homeostasis and numerous studies have associated low blood 25(OH)D concentrations with musculoskeletal function including rickets, osteomalacia, osteopenia, osteoporosis and increased incidence of fractures across the lifespan. However vitamin D receptor (VDR) is expressed in several tissues suggesting a wide range of biological function. Researchers have found that vitamin D status may be associated with other conditions including obesity, insulin resistance, cardiovascular disease and the metabolic syndrome. Low sun exposure, reduced dietary vitamin D intake, and older age are the most common factors associated with vitamin D deficiency (VDD) and the prevalence of VDD is approximately 1 billion worldwide and the rate of insufficiency is higher in female than male population. In the UK 67% of pregnant/lactating women are vitamin D deficient which is worrying as evidence suggests that vitamin D maybe critical for maternal health and normal foetal and/or postnatal development. Fetal vitamin D concentrations are predominantly dependent on maternal levels and there is a growing body of evidence suggesting that suboptimal levels of vitamin D during development can have a negative impact on wellbeing through impacts on muscle and adipose tissues. Vitamin D inadequacy during pregnancy has been associated with increased risk of preeclampsia, development of gestational diabetes and caesarean section in the mother while numerous studies have shown that infants have low birth weights, are small for gestational age, have reduced bone growth, poor skeletal mineralization and lower bone mineral content and by the age of 6 have greater fat mass. While in vivo studies have shown a significant increase in proliferation and lipid droplets in pre-adipocytes from mice exposed to VDD environment during development. Increased lipid deposition within muscle has been associated with functional limitations in muscle performance and an increase in inflammation and atrophy of muscle tissue leading to a decline in muscle functionality. In addition lipid accumulation in skeletal muscle is a significant risk factor for insulin resistance and development of diabetes. The origin and cellular localisation of this fat is unclear, but one possibility is that it forms when myogenic precursor cells present in the muscle transdifferentiate into mature adipocytes as suggested by our previous studies. Low physiological concentrations (a vitamin D deficient state) resulted in increased formation of lipid droplets in C2C12 cells, a muscle cell line, and increased markers of adipogenesis. Thus, we propose that a lack of vitamin D during development may favour adipogenesis at the expense of muscle development. Thus, combining both in vitro and in vivo approaches the aim of this project is to determine whether a lack of vitamin D during pregnancy influences cellular processes involved in the development of skeletal muscle and adipose tissue in the foetuses and whether these subsequently affect energy expenditure and overall body composition of the resulting offspring.