The transcription factor RORα plays an important role in regulating circadian rhythm, inflammation, metabolism, and cellular development. Herein we show a role for RORα-expressing macrophages in the adipose tissue in altering the metabolic state of mice on a high-fat diet. The expression of Rora and RORA is elevated in white adipose tissue from obese mice and humans when compared to lean counterparts. When fed a high-fat diet Rora reporter mice revealed increased expression of Rora -YFP in macrophages in white adipose tissue deposits. To further define the potential role for Rora -expressing macrophages in the generation of an aberrant metabolic state Rora fl/fl LysM Cre/+ mice, which do not express Rora in myeloid cells, were maintained on a high-fat diet, and metabolic parameters assessed. These mice had significantly impaired weight gain and improved metabolic parameters in comparison to Rora fl/fl control mice. Further analysis of the immune cell populations within white adipose tissue deposits demonstrates a decrease in inflammatory adipose tissue macrophages (ATM). In obese reporter mouse there was increased in Rora -YFP expressing ATM in adipose tissue. Analysis of peritoneal macrophage populations demonstrates that within the peritoneal cavity Rora -expression is limited to myeloid-derived macrophages, suggesting a novel role for RORα in macrophage development and activation, which can impact on metabolism, and inflammation.

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Obesity is a prevalent condition with several associated co-morbidities including the development of metabolic diseases. In obesity there is immune cell infiltration into the white adipose tissue and this is associated with the generation of inflammation and insulin resistance (IR). A large majority of the infiltrating leukocytes in obese adipose tissue are pro-inflammatory macrophages, which upon activation induce a switch in metabolism from oxidative phosphorylation, as is utilised by macrophages in lean adipose tissue, towards aerobic glycolysis. The signalling pathways evoked in the recruited macrophages induce the release of pro-inflammatory cytokines, in signalling pathways which directly interfere with insulin signalling and thus induce a state of IR. As macrophages appear to play such a pivotal role in the generation of IR and are the largest leukocyte population in the adipose tissue, they provide a promising therapeutic target. Indeed, there are several strategies currently being studied to induce a 'switch' in macrophages associated with obese adipose tissue, towards the phenotype of those associated with lean adipose tissue, with arguably the most promising being those strategies designed to target the metabolic pathways within the macrophages. This chapter will discuss the polarisation and activation of macrophages within lean and obese adipose tissue and how these cells can be targeted therapeutically.

The transcription factor Related Orphan Receptor Alpha (RORα) plays an important role in regulating circadian rhythm, inflammation, metabolism and cellular development. Herein we show that in the absence of functional RORα in mice there is reduced susceptibility to LPS-induced endotoxic shock, with selective decreases in release of pro-inflammatory cytokines. Treatment of mice with a RORα selective synthetic inhibitor also reduced the severity of LPS-induced endotoxemia. The reduction in responses in Rora deficient mice was associated with an alterations in metabolic and pro-inflammatory functions of macrophages, both in vivo peritoneal macrophages and in vitro generated bone marrow derived macrophages. Using LysMCreRorafl/sg mice the reduced susceptibility to LPS was shown to be specific to Rora expression in the macrophages. This study identifies that Rora-mediated regulation of macrophages impacts on the pro-inflammatory responses elicited by LPS.

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A method of assessing spleen size from splenic scintigraphs obtained using autologous heat damaged 99Tcm labelled red cells is described. The method depends on a "computed volume" estimate. The method has a correlation coefficient of 989 with the exsanguinated weight ofthe spleen after splenectomy and has been shown to have an accuracysuperior to methods previously described.

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