title: Prostaglandin profiling reveals a role for haematopoietic prostaglandin D synthase in adipose tissue macrophage polarisation in mice and humans.
abstract: OBJECTIVE
  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.
  
  
  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.
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors: S
authors: S
authors: Virtue
authors: 1] Medical Research Council Human Nutrition Research, Cambridge, UK [2] Nestlé Institute of Health Sciences, Lausanne, Switzerland.
authors: M
authors: M
authors: Masoodi
authors: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: B A M
authors: BA
authors: de Weijer
authors: Department of Medical Biochemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: M
authors: M
authors: van Eijk
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors: C Y L
authors: CY
authors: Mok
authors: 1] Medical Research Council Human Nutrition Research, Cambridge, UK [2] Metabolomx, Mountain View, CA, USA.
authors: M
authors: M
authors: Eiden
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors: M
authors: M
authors: Dale
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors: A
authors: A
authors: Pirraco
authors: Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: M J
authors: MJ
authors: Serlie
authors: 1] Medical Research Council Human Nutrition Research, Cambridge, UK [2] The Department of Biochemistry, Cambridge, UK.
authors: J L
authors: JL
authors: Griffin
authors: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.
authors: A
authors: A
authors: Vidal-Puig
mesh_terms: D050156:Adipogenesis; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002853:Chromatography, Liquid; D004032:Diet; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000378:metabolism*
chemical_list: D015777:Eicosanoids; D015230:Prostaglandin D2