Role for Retinoic Acid-Related Orphan Receptor Alpha (RORα) Expressing Macrophages in Diet-Induced Obesity

Abstract

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.

Functions for Retinoic Acid-Related Orphan Receptor Alpha (RORα) in the Activation of Macrophages During Lipopolysaccharide-Induced Septic Shock

“…There were no differences in neutrophils and B1a cells in the peritoneum of naive WT and Rora sg/sg mice, with comparable influx of both cells following LPS treatment ( Figure 2A ). However, while there was no differences in the number of resident LPM in naïve WT and Rora sg/sg mice, there were significantly ( P < 0.01) fewer SPM in the peritoneal cavity of naïve Rora sg/sg mice ( Figure 2B ), in accordance with previously published studies ( 8 ). In response to LPS the influx of SPM in the peritoneal cavity was comparable between WT and Rora sg/sg animals ( Figure 2B ).…”

“…Alterations in recruited monocytes has also been observed in the adipose tissue, with myeloid-derived macrophages pro-inflammatory macrophages significantly decreased in the absence of RORα ( 8 ). In both the obesity model and in response to LPS, there is reduced response to the inflammatory stimuli in the absence of RORα.…”

“…RORα has been identified as a transcription factor critical for the development of a number of immune cell populations, including Th17 cells, regulatory T cells, ILC2, ILC3, and macrophage populations (8,21,(32)(33)(34). While RORα may promote intercellular anti-inflammatory signaling pathways, its ability to shape the immune cell repertoire and promote recruitment and activation of pro-inflammatory macrophages demonstrates that RORα also promotes inflammation.…”

“…Indeed, studies on RORα in the context of metabolism have demonstrated the impact of RORα in signaling pathways associated with lipid and glucose metabolism, alongside influencing the low-grade chronic inflammation that is often a hallmark of metabolic disease ( 4 , 7 – 9 ). We have previously demonstrated that Rora -expressing myeloid-derived macrophages play an integral role in metabolic dysfunction associated with obesity ( 8 ). While the expression of RORα in macrophage subsets is now widely observed, there is some disparity in the apparent role of RORα within these cells ( 10 , 11 ).…”

“…In addition, there is evidence that in the context of adipose tissue inflammation, as associated with obesity, RORα is capable of driving inflammation. Indeed, it has been demonstrated that RORα can drive endoplasmic reticulum stress, which promotes adipose tissue inflammation ( 11 ), and in the absence of Rora -expressing myeloid cells, there is a decrease in inflammatory macrophages accumulating in the adipose tissue in a model of obesity ( 8 ). These disparate roles for RORα in similar inflammatory context suggest that the impact of RORα may be modified by tissue- and cell-specific factors.…”