Prostaglandin profiling reveals a role for haematopoietic prostaglandin D synthase in adipose tissue macrophage polarisation in mice and humans

Abstract

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 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 LC-MS/MS 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 of 16 weeks of age. 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 PGD ₂ 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 (ATM). 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 PGD ₂ 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 PGD ₂ in the control of ATM polarisation.