Alhaddad, Ahmad
(2019)
The influence of early life nutrition on adipose tissue development is modulated by age in sheep.
PhD thesis, University of Nottingham.
Abstract
Introduction
Non-shivering thermogenesis in brown adipose tissue (BAT), mediated by a unique uncoupling protein (UCP1), is essential for metabolic adaptation birth in large mammals such as sheep. BAT then undergoes substantial changes as UCP1 is gradually lost and replaced with white adipose tissue (WAT) which mainly acts as a fat storage tissue. Given BAT can be retained into later life a better understanding of this process could enable the maintenance of BAT function by modifying its transition to WAT in early life. Ultimately this could provide a potential target to prevent obesity in adulthood.
Methods
It remains unclear as to whether anatomical location determines a fat depots response to changes in maternal diet during postnatal development. I, therefore, carried out a study that entailed the data mining of microarrays and lipidomic data generated from the major fat depots in young sheep. The sternal, perirenal and epicardial depots were studied, which all possess large amounts of UCP1 at birth and were compared with the subcutaneous depot which has little UCP1 and the omental depot which only appears after birth and does not contain UCP1. This investigation was undertaken by applying machine learning algorithms and weighted gene co-expression networks analyses, during the specific time period of 7 to 28 days of age, which is characterised by the transition of BAT into WAT in young sheep. In addition, I examined whether modifying the mother's milk fat content through fatty acid supplementation, could increase the fatty acid availability and delay the rate at which UCP1 was lost. This was achieved by investigating the impact of supplementing the maternal diet with 3% of canola oil from the day of delivery through the first 28 days of lactation.
Results
By using the gene network analyses, I established that each depot exhibited different gene expression profiles during development. This further demonstrated that the anatomical location modulated this process as each depot displayed succinct arrays of modules consisting of co-expressed gene indicating their unique biological function. It included the capability of mitochondrial biogenesis which was associated with adipocyte differentiation in response to local environmental stimuli. Brown like depots were also distinguished functionally, for lipid metabolism in perirenal, angiogenesis in sternal, and cardiomyocyte cell differentiation in epicardial. In white adipocyte depots, i.e. omental and subcutaneous, high-lighted genes were mainly involved in growth and cell maturation function.
In addition, the result of supplementing the maternal diet with 3% of canola oil revealed a lower rate of loss of mitochondrial gene expression within the sternal, perirenal, omental and subcutaneous depots, specifically in BAT depots (i.e. perirenal and sternal), that enables a high capacity of non-shivering thermogenesis in early life. The lipidomic analyses further demonstrated that the perirenal depot was the only one to exhibit a modified lipid profile to the dietary intervention at 28 days of age when BAT was mostly converted into WAT.
Conclusion
In conclusion, manipulation of the maternal diet by enhancing milk fatty acid content in early life delays losing of mitochondrial genes expression, in the offsprings adipose tissue. This response is modulated by age and anatomical location. These findings suggest that modulating the maternal diet impacts on postnatal fat development, for which the longer term outcomes now need establishing.
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