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亲在早期发育过程中维生素D状态对后代一生健康影响的重要性。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方面具有公认的作用，许多研究已经将低血25(OH)D浓度与肌肉骨骼功能联系在一起，包括软骨病、骨质疏松症、骨质疏松和一生中骨折发生率的增加。然而，维生素D受体(VDR)在多种组织中表达，提示其具有广泛的生物学功能。研究人员发现，维生素D的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。低日晒、膳食维生素D摄入量减少和年龄增大是维生素D缺乏(VDD)的最常见因素，全球VDD的患病率约为10亿，女性VDD缺乏率高于男性。在英国，67%的孕妇/哺乳期妇女缺乏维生素D，这令人担忧，因为有证据表明，维生素D可能对产妇健康和正常的胎儿和/或出生后发育至关重要。胎儿的维生素D浓度主要取决于母亲的水平，越来越多的证据表明，发育期间维生素D的水平低于最佳水平，可能会通过影响肌肉和脂肪组织而对健康产生负面影响。孕期维生素D不足与母亲患先兆子痫、妊娠期糖尿病和剖腹产的风险增加有关，而许多研究表明，婴儿出生体重低，胎龄较小，骨骼生长减慢，骨骼矿化不良，骨矿物质含量较低，6岁时脂肪较多。而体内研究表明，在发育过程中，暴露于VDD环境的小鼠前脂肪细胞的增殖和脂滴显着增加。肌肉内脂肪沉积的增加与肌肉表现的功能受限以及肌肉组织炎症和萎缩的增加导致肌肉功能下降有关。此外，骨骼肌中的脂肪堆积是胰岛素抵抗和糖尿病发展的重要危险因素。这种脂肪的来源和细胞定位尚不清楚，但一种可能性是，正如我们之前的研究所表明的那样，它是在肌肉中存在的肌源性前体细胞转分化为成熟脂肪细胞时形成的。低生理浓度(维生素D缺乏状态)导致肌肉细胞系C2C12细胞中脂滴的形成增加，脂肪生成的标记物增加。因此，我们认为在发育过程中缺乏维生素D可能以牺牲肌肉发育为代价促进脂肪生成。因此，结合体外和体内方法，该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由此产生的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.