title: Macrophage-derived factors impair insulin signalling pathway in human adipose cells: role of IL-1β
Creators: name: Madi, MF
Publisher: name: University of Liverpool Repository
Year: 2016

description: ABSTRACT The prevalence of obesity and overweight has dramatically increased throughout the world and becomes a major health concern. In obesity, adipose tissue expansion is associated with increased macrophage infiltration and marked change in cytokine/chemokine production. Macrophage-derived factors significantly alter adipose cells function, inducing inflammatory responses, reducing insulin sensitivity and impairing differentiation capability which may contribute to obesity-related metabolic disorder such as insulin resistance and type 2 diabetes. Human adipose cells (preadipocytes and adipocytes) play an important role in adipose tissue remodelling but their role in the development of insulin resistance and type 2 diabetes remains to be established. Identification of the major factors that mediate the detrimental effects of macrophages on adipose cells may offer potential therapeutic targets. IL-1β, a pro-inflammatory cytokine, is suggested to be involved in the development of insulin resistance. In this thesis, different models of cells in adipose tissue were used to establish the effect of the crosstalk between them on the function of adipose cells, including human primary preadipocytes, adipocytes, THP-1 macrophages (cell line) and peripheral blood-derived macrophages. More specifically, this work investigated the role of IL-1β in macrophage-adipose cells cross-talk which affects the insulin signalling pathway, inflammatory response and adipocyte development in adipose tissue. The results presented in this thesis reveal that basal expression of insulin signalling proteins (IR, IRS-1 and PI3K-p85α) was present and detectable in both human adipose cells. IL-1β modulated the expression of insulin signalling proteins including IR (Y1185), IRS-1(Ser612) and Akt (Ser473) in human preadipocytes upon insulin stimulation. Furthermore, IL-1β mediated macrophage-induced modulation of the insulin signalling molecules in human preadipocytes. In mature adipocytes, IL-1β significantly modulated protein abundance of insulin signalling molecules, including IRS-1, PI3K-p85α and Glut4 and phosphorylation of IR and Akt. In addition, IL-1β mediated macrophage-induced expression and release of the pro-inflammatory cytokine/chemokines (IL-6, IL-8, MCP-1 and RANTES) in both human adipose cells. Blocking IL-1β activity, its receptor binding and production can partially or totally restore the expression of insulin signalling proteins and insulin responsiveness in both adipose cells. IL-1β antagonism also protected against macrophage-stimulated release of the pro-inflammatory cytokines/chemokines and macrophage-inhibited release of adiponectin. Additionally, both IL-1β and MC medium reduced lipid accumulation by reducing expression of the adipogenic factors including C/EBPα, PPARγ and aP2 and stimulating lipolysis in human adipocytes. In conclusion, the results of this thesis suggest that IL-1β mediates, at least in part, the effect of macrophages on insulin signalling and pro-inflammatory response in human adipose cells. Therefore, blocking IL-1β may serve as a beneficial target for reducing obesity-associated inflammation and insulin resistance in human adipose tissue.