Introduction: Obesity and related cardio-metabolic complications have acquired global epidemic proportions. Suboptimal nutritional environment in early life induces adaptations in energy homeostasis, metabolism and adipose tissue development that may confer short-term survival advantages but are detrimental in later life, particularly if nutrient supply is restored. Brown adipose tissue (BAT) has a unique role in energy homeostasis because it can provide a potential compensatory mechanism against excess weight gain via cold or diet-induced adaptive thermogenesis. Brown adipocytes also have a potential role in lipid and glucose metabolism and BAT activation can increase clearance of lipids and glucose from the circulation. Pericardial fat, particularly epicardial adipose tissue (fat present between the myocardium and the visceral layer of the pericardium), is anatomically and clinically related to cardiac morphology and function and is believed to be a metabolically active organ that affects cardiac function and the evolution of cardiac pathologies. High expression of mRNA for uncoupling protein (UCP) 1 in adult human epicardial adipose tissue suggests that this may be a depot of BAT. Hypotheses: In my thesis, I hypothesised that pericardial adipose tissue is a depot of brown fat in humans and sheep. I also hypothesised that suboptimal nutrition in early life will affect adiposity and development of BAT in this depot. Methods: UCP1 mRNA expression and protein abundance and other BAT and white adipose tissue related genes were studied in pericardial adipose tissue. In the first study, pericardial fat was sampled from newborn and 30 day old sheep born to mothers fed with 100% or 60% of their total metabolisable energy (ME) requirement from 110 day gestation to term. In the second study, pericardial fat was sampled from near-term (140 day gestation) fetuses delivered to mothers fed 100% or 60% of total ME requirement from 28 to 80 days and then fed ad libitum. Gene expression was measured by reverse transcription-polymerase chain reaction and protein abundance by Western blotting and immunohistochemistry. To confirm the presence of BAT in the human epicardial fat depot, relative abundance of UCP1 was measured by Western Blotting in epicardial, paracardial, and subcutaneous fat samples taken from adults. In the final study, epicardial fat samples were collected from 63 children (0-18 years of age) undergoing cardiac surgery and gene expression of UCP1 and other BAT and WAT related genes identified by microarray. The presence of UCP1 was confirmed by immunohistochemistry. Results: Pericardial adipose tissue is a depot of BAT in fetal and newborn sheep. Suboptimal maternal nutrition in late gestation reduces the abundance of UCP1 and downregulates other BAT related genes whilst suboptimal maternal nutrition in early-to-mid gestation followed by ad libitum feeding to term, increases adiposity, enhances UCP1 abundance and upregulates genes involved in brown and white adipogenesis. Epicardial fat from newborn infants, children, adolescents and older adults contains UCP1 confirming that it is a BAT depot in humans. UCP1 gene expression in infancy and early childhood in humans is downregulated in children with poor nutritional states. Conclusions: I have shown that adipose tissue depots present around the heart are a repository of brown fat, at least in humans and sheep. In view of the potential role of BAT in regulation of lipid and glucose metabolism, this may have therapeutic implications for treatment of cardiovascular complications of obesity. Suboptimal nutrition in utero and during early life compromises BAT development. Although the exact mechanism of how these changes affect the propensity towards obesity and metabolic dysregulation remains to be elucidated, a reduction in thermogenesis presents a plausible mechanism for the increased metabolic efficiency associated with nutritional deprivation in early life. BAT persists beyond the neonatal period in to adult life and, therefore, presents a potential target for long lasting nutritional manipulations to promote better health.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:677946 |
| Date | January 2015 |
| Creators | Ojha, Shalini |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/30678/ |
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