Clinical Bioinformatics Area, Fundación Progreso y Salud, CDCA, Hospital Virgen del Rocio, Sevilla, Spain; Functional Genomics Node, INB-ELIXIR-es, FPS, Hospital Virgen del Rocio, Sevilla, Spain; Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Sevilla, Spain
Department of Medicine, Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
Joaquin Dopazo
Clinical Bioinformatics Area, Fundación Progreso y Salud, CDCA, Hospital Virgen del Rocio, Sevilla, Spain; Functional Genomics Node, INB-ELIXIR-es, FPS, Hospital Virgen del Rocio, Sevilla, Spain; Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Sevilla, Spain
Mireille J Serlie
Department of Endocrinology and Metabolism, Amsterdam University Medical Center, Amsterdam, Netherlands
Albert Koulman
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, United Kingdom
University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom
White adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs isolated from obese mice and humans exhibit markers of increased rate of de novo phosphatidylcholine (PC) biosynthesis. Macrophage-specific knockout of phosphocholine cytidylyltransferase A (CCTα), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCTα-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCTα-null macrophages had lower membrane PC turnover, leading to elevated membrane polyunsaturated fatty acid levels that negated the pro-inflammatory effects of palmitate. Our results reveal a causal link between obesity-associated increase in de novo PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs.
