Prostaglandin profiling reveals a role for haematopoietic prostaglandin D synthase in adipose tissue macrophage polarisation in mice and humans.
de Weijer, BAM
van Eijk, M
Int J Obes (Lond)
Nature Publishing Group
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Virtue, S., Masoodi, M., de Weijer, B., van Eijk, M., Mok, C., Eiden, M., Dale, M., et al. (2015). Prostaglandin profiling reveals a role for haematopoietic prostaglandin D synthase in adipose tissue macrophage polarisation in mice and humans.. Int J Obes (Lond), 39 1151-1160. https://doi.org/10.1038/ijo.2015.34
BACKGROUND/OBJECTIVES: Obesity has been associated with both changes in adipose tissue lipid metabolism and inflammation. A key class of lipid-derived signalling molecules involved in inflammation are the prostaglandins. In this study, we aimed to determine how obesity affects the levels of prostaglandins within white adipose tissue (WAT) and determine which cells within adipose tissue produce them. To avoid the effects of cellular stress on prostaglandin levels, we developed a multivariate statistical approach in which metabolite concentrations and transcriptomic data were integrated, allowing the assignment of metabolites to cell types. SUBJECTS/METHODS: Eicosanoids were measured by liquid chromatography-tandem mass spectrometry and mRNA levels using real-time PCR. Eicosanoid levels and transcriptomic data were combined using principal component analysis and hierarchical clustering in order to associate metabolites with cell types. Samples were obtained from C57Bl/6 mice aged 16 weeks. We studied the ob/ob genetically obese mouse model and diet-induced obesity model. We extended our results in mice to a cohort of morbidly obese humans undergoing bariatric surgery. RESULTS: Using our modelling approach, we determined that prostglandin D₂ (PGD₂) in adipose tissue was predominantly produced in macrophages by the haematopoietic isoform of prostaglandin D synthase (H-Pgds). Analysis of sub-fractionated WAT confirmed that H-Pgds was expressed in adipose tissue macrophages (ATMs). Furthermore, H-Pgds expression in ATMs isolated from lean and obese mice was consistent with it affecting macrophage polarisation. Functionally, we demonstrated that H-PGDS-produced PGD₂ polarised macrophages toward an M2, anti-inflammatory state. In line with a potential anti-inflammatory role, we found that H-PGDS expression in ATMs was positively correlated with both peripheral insulin and adipose tissue insulin sensitivity in humans. CONCLUSIONS: In this study, we have developed a method to determine the cellular source of metabolites within an organ and used it to identify a new role for PGD₂ in the control of ATM polarisation.
HQL-79 was a kind gift of Professor Yoshihiro Urade. Professor Vidal-Puig was funded by the BHF, MRC and BBSRC. Dr Virtue was funded by the BBSRC and the BHF. Dr Eiden, Dr Masoodi and Dr Griffin were funded by the MRC. Dr Mok was funded by the Wellcome Trust.
British Heart Foundation (None)
Medical Research Council (MC_G0802535)
Medical Research Council (MC_UU_12012/2)
Biotechnology and Biological Sciences Research Council (BB/H002731/1)
Medical Research Council (G0400192)
Biotechnology and Biological Sciences Research Council (BB/H013539/1)
Medical Research Council (G0802051)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_PC_13030)
External DOI: https://doi.org/10.1038/ijo.2015.34
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247835
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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