The role of adipose tissue in the metabolism of fatty acid hydroxy fatty acids in humans

Excess adiposity is associated with the metabolic syndrome and type 2 diabetes and hence to the rising healthcare burden of those and related diseases. Consequently, adipose tissue (AT) and its role in glycaemic control and systemic inflammation is an important area of contemporary research.
Recently, a novel family of endogenously-synthesised lipids was identified. Fatty acid-hydroxy fatty acids (FAHFAs) have been shown, with acute treatment, to reduce glycaemia in mice by a mechanism which increased translocation of the GLUT4 glucose transporter to the cell membrane of adipocytes and which involves the free fatty acid receptor 4 (FFAR4). In humans, it has been suggested that plasma levels of certain FAHFAs are lower in individuals with reduced insulin sensitivity but this was not replicated in another study. It has also been suggested that the plasma levels of FAHFAs are lower in morbidly obese people. Mechanistic studies in vitro with murine cells have also shown equivocal results with FAHFA treatments either inhibiting or enhancing lipolysis, a key process in adipocytes. Additionally, it is suggested that de novo lipogenesis (DNL), another key process, is also affected by FAHFAs. Little is known about the distribution or composition of FAHFAs in the blood and AT, nor of their synthesis and degradation.
In order to better understand FAHFA distribution in humans and to clarify their association with insulin resistance and other measures of metabolic health and phenotype, I examined plasma and adipose tissue FAHFA concentrations in healthy adults with a range of body mass index. In addition, I optimised in vitro adipocyte culture conditions and used both primary human cells from biopsies and immortalised preadipocytes to test the effect of FAHFAs on adipocyte function.
In vivo, I found plasma FAHFAs to be higher in men than women. There was no association between fasting plasma FAHFAs and insulin sensitivity, and some evidence that plasma FAHFAs may increase with increasing adiposity in women. Fasting plasma FAHFAs were not correlated with plasma fatty acids despite expectations that they would be regulated in a similar manner. In vitro, FAHFAs were found to inhibit lipolysis, as insulin does, but, in contrast to insulin, FAHFAs inhibited DNL. The capacity to synthesise FAHFAs was similar between the abdominal and gluteal adipocytes but there was a suggestion, from the AT biopsies, that the concentrations of FAHFAs may be higher in abdominal than in gluteal AT.
Overall, my work has added further to the knowledge of the distribution of FAHFAs in the body and their relationship to phenotype in humans. There were only weak relationships between plasma FAHFAs and either insulin sensitivity or adiposity and the directions of these were opposite to previous reports, suggesting that, if these associations are substantiated in vivo, then they are probably complex and multifactorial. I have uncovered some aspects of FAHFAs which differ between the sexes or between the AT depots, which should be borne in mind for future research. In examining the effect of FAHFAs in adipocytes, I have identified an effect on DNL which merits further investigation.

Advisor: Hodson, L
Pinnick, K