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.
-
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.
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.
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.
Metrics
-
- 5,163
- views
-
- 617
- downloads
-
- 50
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity
eLife 8:e47990.
https://doi.org/10.7554/eLife.47990
Further reading
-
- Cell Biology
- Developmental Biology
Eukaryotic cells depend on exocytosis to direct intracellularly synthesized material toward the extracellular space or the plasma membrane, so exocytosis constitutes a basic function for cellular homeostasis and communication between cells. The secretory pathway includes biogenesis of secretory granules (SGs), their maturation and fusion with the plasma membrane (exocytosis), resulting in release of SG content to the extracellular space. The larval salivary gland of Drosophila melanogaster is an excellent model for studying exocytosis. This gland synthesizes mucins that are packaged in SGs that sprout from the trans-Golgi network and then undergo a maturation process that involves homotypic fusion, condensation, and acidification. Finally, mature SGs are directed to the apical domain of the plasma membrane with which they fuse, releasing their content into the gland lumen. The exocyst is a hetero-octameric complex that participates in tethering of vesicles to the plasma membrane during constitutive exocytosis. By precise temperature-dependent gradual activation of the Gal4-UAS expression system, we have induced different levels of silencing of exocyst complex subunits, and identified three temporarily distinctive steps of the regulated exocytic pathway where the exocyst is critically required: SG biogenesis, SG maturation, and SG exocytosis. Our results shed light on previously unidentified functions of the exocyst along the exocytic pathway. We propose that the exocyst acts as a general tethering factor in various steps of this cellular process.
-
- Cell Biology
Multiple gut antimicrobial mechanisms are coordinated in space and time to efficiently fight foodborne pathogens. In Drosophila melanogaster, production of reactive oxygen species (ROS) and antimicrobial peptides (AMPs) together with intestinal cell renewal play a key role in eliminating gut microbes. A complementary mechanism would be to isolate and treat pathogenic bacteria while allowing colonization by commensals. Using real-time imaging to follow the fate of ingested bacteria, we demonstrate that while commensal Lactiplantibacillus plantarum freely circulate within the intestinal lumen, pathogenic strains such as Erwinia carotovora or Bacillus thuringiensis, are blocked in the anterior midgut where they are rapidly eliminated by antimicrobial peptides. This sequestration of pathogenic bacteria in the anterior midgut requires the Duox enzyme in enterocytes, and both TrpA1 and Dh31 in enteroendocrine cells. Supplementing larval food with hCGRP, the human homolog of Dh31, is sufficient to block the bacteria, suggesting the existence of a conserved mechanism. While the immune deficiency (IMD) pathway is essential for eliminating the trapped bacteria, it is dispensable for the blockage. Genetic manipulations impairing bacterial compartmentalization result in abnormal colonization of posterior midgut regions by pathogenic bacteria. Despite a functional IMD pathway, this ectopic colonization leads to bacterial proliferation and larval death, demonstrating the critical role of bacteria anterior sequestration in larval defense. Our study reveals a temporal orchestration during which pathogenic bacteria, but not innocuous, are confined in the anterior part of the midgut in which they are eliminated in an IMD-pathway-dependent manner.
