Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity
- University of Cambridge, United Kingdom
- Fundacion Progreso y Salud, Spain
- Karolinska Institute, Sweden
- Amsterdam University Medical Center, Netherlands
Abstract
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 (CCTa), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCTa-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, CCTa-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.
Data availability
We are submitting raw source data excel file for LC-MS lipidomics of Pcyt1a-deficient BMDMs, in both palmitate-treated and basal states (containing peak areas for each lipid species normalized to peak areas of respective internal standards) as Figure 6-source data 1.ATM microarray dataset (GSE36669) used in Figure 1 is already published and referenced in this manuscript.We are also submitting a list of differentially expressed genes detected by RNAseq in the eWAT of ob/ob bone marrow transplant mice, with a log (Fold change), log (CPM) and p value indicated for each gene as Supplementary file 2b.We have uploaded raw RNA sequencing data of liver macrophages isolated from WT and ob/ob mice in the NCBI database, under the following accession number: PRJNA541224.
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Ob/ob liver macrophage RNA sequencingNCBI BioProject, PRJNA541224.
Article and author information
Author details
Cecilia Morgantini
Antonio Vidal-Puig
Funding
Wellcome (4-year PhD programme in Metabolic and Cardiovascular Disease)
- Kasparas Petkevicius
British Heart Foundation (Programme Grant RG/18/7/33636)
- Kasparas Petkevicius
- Sam Virtue
- Guillaume Bidault
- Antonio Vidal-Puig
Wellcome (Strategic Award)
- Kasparas Petkevicius
- Sam Virtue
- Guillaume Bidault
- Antonio Vidal-Puig
Medical Research Council (MRC_MC_UU_12012/5)
- Kasparas Petkevicius
- Sam Virtue
- Guillaume Bidault
- Antonio Vidal-Puig
Medical Research Council (MRC_MC_UU_12012/2)
- Kasparas Petkevicius
- Sam Virtue
- Guillaume Bidault
- Antonio Vidal-Puig
Spanish Ministry of economy and competitiveness (SAF2017-88908-R)
- Cankut Çubuk
- Joaquin Dopazo
Swedish Research council (2015-03582)
- Cecilia Morgantini
- Myriam Aouadi
Strategic research program in Diabetes at Karolinska Institutet (M.A.)
- Cecilia Morgantini
- Myriam Aouadi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Michael Czech, University of Massachusetts Medical School, United States
Ethics
Animal experimentation: All animal protocols were conducted in accordance with the UK Home Office and Cambridge University ethical guidelines.
Human subjects: Human samples used for this work had been generated as part of another study, that has already been published and is referenced in our manuscript (de Weijer et al, 2013). This study had been conducted to the highest ethical standards, and the ethics statement is available in the published paper.
Version history
- Received: April 26, 2019
- Accepted: August 15, 2019
- Accepted Manuscript published: August 16, 2019 (version 1)
- Version of Record published: September 17, 2019 (version 2)
Copyright
© 2019, Petkevicius et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity
eLife 8:e47990.
https://doi.org/10.7554/eLife.47990
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