Pro-/anti-inflammatory signalling pathways in brown and white adipocytess

Brown adipose tissue (BAT) and beige adipocytes offer an appealing prospect to combat obesity and associated metabolic diseases through its thermogenic capacity. A state of low-grade chronic inflammation is described in obesity with increasing evidence that inflammation directly alters the thermogenic activity of BAT. As such, gut-derived lipopolysaccharide (LPS) could be among the triggers of proinflammatory status and may contribute to BAT dysfunction in obesity as it has been previously reported to be elevated in obesity. In contrast, Activation of GPR120, a G protein-coupled receptor, by TUG-891 or other agonists mediates anti-inflammatory actions and enhances the metabolic activity of BAT, representing a potential treatment to reduce adipocyte dysfunction in obesity. Therefore, the aims of this thesis were (1) to investigate the effects of LPS on brown adipocyte biology and secretory function, (2) to identify the impact of LPS on the induction of beige adipocytes, (3) to explore GPR120 activation via TUG-891 as therapeutic potential against brown adipocyte dysfunction. With the use of cutting-edge laboratory technology, the outcome of this study elucidated that LPS is a potent inhibitor of the brown phenotype, insulin sensitivity, mitochondrial function and the browning process in white adipocytes. Additionally, the analysis of a wide spectrum of LPS effects revealed that thermogenesis and extracellular matrix (ECM)-receptor interaction are among the top downregulated pathways as well as inflammatory microenvironment results from cytokine secretion from brown adipocytes themselves. BAFF, CXCL5, CXCL16 and MMP3 were identified as novel brown adipocyte-secreted cytokines and may target thermogenic potential of brown adipocytes. Finally, TUG-891, a GPR120 agonist, showed effectiveness in reversing LPS damaging actions. In conclusion, this study provides evidence that LPS-induced inflammation directly alters the thermogenic components of brown adipocytes at transcriptional and functional levels. Targeting GPR120 via TUG-891 offers a promising strategy to protect against the detrimental effects of LPS. Ultimately, combating the effects of inflammation in BAT could help in reducing obesity and its consequences