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

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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.