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Title: Metabolic adaptations of pregnancy
Author: Nikolova, Vanya Toncheva
ISNI:       0000 0004 5372 0562
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Pregnancy is a complex biological condition associated with profound changes in the metabolism of the mother, essential for the growth and development of the fetoplacental unit. We aimed to study molecular pathways that contribute to the gestational alterations in lipid metabolism. The data in this report show that adaptations in lipid homeostasis during mouse pregnancy include raised hepatic cholesterol content, decreased levels of circulating cholesterol and elevated serum triglycerides. Moreover, LXR signalling contributes to the enhanced lipogenesis in early mouse pregnancy by increasing fatty acid biosynthesis in the liver. There is a gradual down-regulation of LXR targets involved in hepatic lipogenesis, cholesterol uptake and clearance following mouse placenta formation. Pharmacological activation of LXR not only blunted the reduction of these genes but also reversed the changes in hepatic and serum lipid profiles observed during normal murine pregnancy. Our results strongly suggest that LXR signalling is altered during mouse pregnancy and this is an essential adaptation to facilitate altered maternal lipid homeostasis. Investigations were performed to establish whether maternal metabolic adaptations in energy homeostasis result from altered diurnal fluctuations in peripheral metabolic pathways. We show that pregnancy alters the activity of core clocks in liver, white adipose tissue and skeletal muscle. Early and advanced pregnancy changes the diurnal fluctuations in the expression of key metabolic genes in the liver in order to enhance or dampen lipogenesis respectively during these gestational periods. We present preliminary data suggesting that the temporal oscillations in bile acid metabolism are shifted during pregnancy independently of feeding patterns. Moreover, fatty acid homeostasis in skeletal muscle is changed during early pregnancy possibly as a consequence of the REV-ERBβ-dependent downregulation of Cpt1β-mediated lipid oxidation. Also, placenta lipid homeostasis exhibits robust temporal oscillations so that pathways mediating fatty acid and cholesterol transport as well as triglyceride hydrolysis become activated during the dark phase. Subcutaneous and visceral white adipose tissue depots were examined to determine whether metabolic pathways in these tissues are differentially regulated during non-complicated pregnancy and gestational cholestasis. We show evidence that although both of these depots expand in the course of gestation in order accommodate triglyceride accrual, subcutaneous fat develops a pro-inflammatory phenotype whereas visceral fat remains quiescent. Feeding of pregnant mice with a cholic acid-supplemented diet raises their serum triglyceride and free fatty acid levels and reduces adipose tissue lipogenesis. Gestational cholestasis also decreases white fat inflammation in a depot-specific manner and interferes with adipose tissue remodelling and expansion. We concluded that failure of fat to grow and store surplus lipids that normally accrue during pregnancy could contribute to the development of cholestatic dyslipidaemia.
Supervisor: Williamson, Catherine Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available