Impact of maternal vitamin D deficiency on body composition: the role of neuronal development in appetite regulation

母亲维生素D缺乏对身体成分的影响：神经元发育在食欲调节中的作用。这项研究计划的总体目标是确定母亲在早期发育期间的维生素D状态对后代整个生命周期的健康的重要性。具体地说，我们将结合体外和体内的方法，研究怀孕期间缺乏维生素D如何影响胎儿神经元发育的细胞过程，以及随后对后代食欲调节和身体组成的影响。维生素D的状态由血清中25-羟基维生素D的水平决定，低水平的维生素D与肌肉骨骼疾病有关，包括软骨病、骨软化症、骨量减少、骨质疏松症和一生中骨折发生率的增加。然而，维生素D受体(VDR)在几个组织中表达，提示了广泛的生物学功能。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、痴呆症、帕金森氏症、自闭症、精神分裂症、心血管疾病、代谢综合征、癌症和自身免疫性疾病。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。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，骨骼矿物质含量较低。此外，在9岁时，母亲缺乏维生素D与更高的肥胖症和I型糖尿病有关。活性维生素D(1，25(OH)2D)可以与大脑基本食欲和认知区域(包括海马体、下丘脑和大脑皮层)的神经元和神经胶质细胞上的受体结合，触发神经元保护。动物研究表明，来自VDD母鸡的胚胎使胎儿大脑变大，可能是由于细胞凋亡水平降低，减数分裂增加，神经营养因子(神经生长因子，NGF)水平下降。要研究的问题是“大脑发育改变是否会导致食欲中枢的改变，从而导致后代肥胖增加？”事实上，下丘脑中NGF的减少与小鼠的肥胖有关，因为NGF基因敲除的小鼠患上了与食物摄入量增加和能量消耗减少相关的迟发性肥胖症。而VDD被证明有利于脂肪细胞的沉积，可能是由于刺激了刺鼠相关蛋白和神经肽Y，而抑制了前阿片黑素皮质素。因此，本博士的目标是利用体外和体内模型，确定维生素D缺乏对大脑发育相关的生理功能和分子机制的影响，以及对食欲行为和身体组成的影响。

Impact of maternal vitamin D deficiency on body composition: the role of neuronal development in appetite regulation.The overall aim of the research proposal is to determine the importance of maternal vitamin D status during early development on health across the lifespan of offspring. Specifically, we will investigate how lack of vitamin D during pregnancy influences cellular processes of neuronal development in the foetuses and subsequent effects on appetite regulation and body composition in the offspring, combining in vitro and in vivo approaches. Vitamin D status is determined by the serum level of 25-hydroxyvitamin D, and low vitamin D levels has been associated with musculoskeletal disorders including rickets, osteomalacia, osteopenia, osteoporosis and increased incidence of fractures across the lifespan. However the 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, dementia, Parkinson's disease, autism, schizophrenia, cardiovascular disease, the metabolic syndrome, cancer and autoimmune diseases. 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. 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, being small for gestational age, have reduced bone growth, poor skeletal mineralization and lower bone mineral content. Additionally by 9 years of age, maternal vitamin D deficiency is associated with higher adiposity and type I diabetes. Active vitamin D (1,25(OH)2D) can bind to receptors in neuronal and glial cells throughout the essential appetitive and cognitive regions of the brain (including the hippocampus, hypothalamus, and cortex) triggering neuronal protection. Animal studies have indicated that embryos from VDD dams have enlarged fetal brains, possibly due to decreased levels of apoptosis, increased meiosis and decreased levels of the neurotrophin, nerve growth factor NGF). The question to be investigated is "Does altered brain development lead to changes in appetite centres which lead to increased adiposity observed in the offspring?" Indeed, decreased NGF in the hypothalamus has been associated with obesity in mice, as NGF knockout mice develop late onset obesity associated with increased food intake and decreased energy expenditure. While VDD has been shown to favour adipocyte deposition possibly due to the stimulation of agouti-related protein and neuropeptide Y while suppressing pro-opiomelanocortin. Thus the objective of this PhD is to determine the effects of exposure to vitamin D deficiency on physiological functions and molecular mechanisms associated with brain development and its effects on appetitive behaviour and body composition using both in vitro and in vivo models.