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 Rorafl/flLysMCre/+ 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 Rorafl/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.
Highlights
The transcription factor retinoic acid receptor-related orphan receptor alpha (RORα) is a member of the nuclear hormone receptor superfamily, which provides a bridge between hormonal, nutritional, and pathophysiological signaling and gene regulation
The decreased adiposity in these mice is associated with decreased triglyceride deposition and reduced expression of a number of genes associated with lipid metabolism, including apolipoprotein A-1 and apolipoprotein CIII [22, 23]
We demonstrate a novel role for RORα in promoting metabolic dysfunction in a mouse model of obesity, through expression in myeloid-derived inflammatory and metabolically active macrophages in the adipose tissue
Summary
The transcription factor retinoic acid receptor-related orphan receptor alpha (RORα) is a member of the nuclear hormone receptor superfamily, which provides a bridge between hormonal, nutritional, and pathophysiological signaling and gene regulation. RORα itself has been identified as having roles in neural development, metabolism, cellular differentiation, immune regulation, and circadian rhythm. Staggerer mice (Rorasg/sg), which express a truncated form of the RORα protein due to a spontaneous mutation in the Rora gene, show aberrant immune responses [1,2,3,4]. Studies on RORα in the context of immunity have focused primarily on two aspects; regulation of immune signaling pathways, and involvement in immune cell development. Expression of RORα is induced in tissue and cells, including macrophages, in response to inflammatory stimuli, suggesting a role in the immune response [5, 6]. RORα has been implicated in the inflammatory response to the TLR agonist lipopolysaccharide (LPS) through its ability to down-modulate NF-κB signaling and impair activation of the NLRP3 inflammasome [1, 2, 5]
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