Obesity and type 2 diabetes (T2DM) are both inflammatory disorders with parallel escalating epidemics. Novel insights provided by the new biology suggest common pathways by which several pathogenic components of obesity affect glucose metabolism and cellular responsiveness to insulin leading eventually to the development of T2DM; inflammation is considered critical for the development of the above metabolic disorders and is directly influenced by weight gain. Adipose tissue (AT), particularly the abdominal fat depot is currently considered source of inflammatory agents that fuel whole body’s low grade inflammatory state. The HLA-B Associated Transcript 1 (BAT1) is a cellular member of the DExD/H-box RNA-helicases with essential role for cellular mRNA export, that also attains anti-inflammatory properties, as it was shown by studies investigating monocytes and T-cell lines. Furthermore, BAT1 polymorphisms were linked to predisposition to immunopathologic disorders including type 1 diabetes. These findings suggest a potential protective role of BAT1 against the obesity-associated lowgrade inflammatory state that contributes to T2DM development. The role of BAT1 in the adipocytes has not been investigated so far. Therefore, this thesis examined BAT1 expression and regulation within specific human AT depots and the adipocyte itself. Initial studies indicated BAT1 expression in ex vivo human AT but also the repressing effect of increasing adiposity and T2DM on BAT 1 expression. Remarkably, there was no difference in BAT1 expression between obese subjects and patients with T2DM indicating that BAT1 becomes suppressed with increasing adiposity and remains suppressed through to the development of T2DM and thereafter; this could in turn reduce the capacity to response to the inflammatory insults. As human AT contains many different types of cells besides adipocytes, including fibroblasts, macrophages, lymphocytes, pre-adipocytes and endothelial cells, some of which actually increase with increasing adiposity (e.g. macrophages and lymphocytes) subsequent studies determined the expression of BAT1 particularly in isolated human primary pre-adipocytes and mature adipocytes; the human pre-adipocyte cell line Chub- S7 was used for this purpose. It was shown that BAT1 (mRNA and protein) was expressed in both cell types with maximum expression in mature (lipid accumulating) adipocytes. At the stage of complete maturation, the effects of nutrients and inflammatory factors on BAT1 expression were examined. Both glucose and non-esterified fatty acids (NEFA) were shown to repress BAT 1; these findings were in keeping with the ex vivo data determined in terms of AT from obese and T2DM subjects. Furthermore, these studies indicated a synergistic action of both JNK and NFκB when used in combination to reduce BAT1 expression, indicating interconnectivity between JNK and NFκB pathways, as noted in other human AT studies examining other molecules. Regarding NEFA however, the JNK pathway seemed to mediate its repressing effect on BAT1. These studies also showed that the potent inflammatory agent lipopolysacharide (LPS) also significantly reduced BAT1 expression which was again in keeping with the previous ex vivo AT data since LPS is raised in conditions of metabolic disease. Finally, the investigation of the paracrine influences of leptin and resistin on differentiated primary adipocytes highlighted BAT 1 repression whilst adiponectin appeared to have no significant effect alone to alter BAT 1 expression or inhibit LPS-induced BAT1 repression. Taken together, BAT1 was more susceptible to the repressing effects of nutritional factors (glucose and NEFA) in excess than paracrine inflammatory or antiinflammatory adipokines. The fact that several factors modulate BAT1 expression may suggest that BAT1 represents a first line, non-selective, cellular protective agent, which is therefore influenced by several different factors through common inflammatory pathways. Thus, BAT1 suppression may be an early key event in the pathogenesis of a low chronic inflammatory state. As such BAT1 could represent an important target to manipulate to combat the low chronic inflammatory state observed in both obese and T2DM patients.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:560341 |
| Date | January 2012 |
| Creators | Lois, Konstantinos |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/49631/ |
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