Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation
Open accessAbstract
OBJECTIVE: A novel approach to regulate obesity-associated adipose inflammation may be through metabolic reprogramming of macrophages (MΦs). Broadly speaking, MΦs dependent on glucose are pro-inflammatory, classically activated MΦs (CAM), which contribute to adipose inflammation and insulin resistance. In contrast, MΦs that primarily metabolize fatty acids are alternatively activated MΦs (AAM) and maintain tissue insulin sensitivity. In actuality, there is much flexibility and overlap in the CAM-AAM spectrum in vivo dependent upon various stimuli in the microenvironment. We hypothesized that specific lipid trafficking proteins, e.g. fatty acid transport protein 1 (FATP1), would direct MΦ fatty acid transport and metabolism to limit inflammation and contribute to the maintenance of adipose tissue homeostasis. METHODS: Bone marrow derived MΦs (BMDMs) from Fatp1 (-/-) and Fatp1 (+/+) mice were used to investigate FATP1-dependent substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. We also generated C57BL/6J chimeric mice by bone marrow transplant specifically lacking hematopoetic FATP1 (Fatp1 (B-/-)) and controls Fatp1 (B+/+). Mice were challenged by high fat diet (HFD) or low fat diet (LFD) and analyses including MRI, glucose and insulin tolerance tests, flow cytometric, histologic, and protein quantification assays were conducted. Finally, an FATP1-overexpressing RAW 264.7 MΦ cell line (FATP1-OE) and empty vector control (FATP1-EV) were developed as a gain of function model to test effects on substrate metabolism, bioenergetics, metabolomics, and inflammatory responses. RESULTS: Fatp1 is downregulated with pro-inflammatory stimulation of MΦs. Fatp1 (-/-) BMDMs and FATP1-OE RAW 264.7 MΦs demonstrated that FATP1 reciprocally controled metabolic flexibility, i.e. lipid and glucose metabolism, which was associated with inflammatory response. Supporting our previous work demonstrating the positive relationship between glucose metabolism and inflammation, loss of FATP1 enhanced glucose metabolism and exaggerated the pro-inflammatory CAM phenotype. Fatp1 (B-/-) chimeras fed a HFD gained more epididymal white adipose mass, which was inflamed and oxidatively stressed, compared to HFD-fed Fatp1 (B+/+) controls. Adipose tissue macrophages displayed a CAM-like phenotype in the absence of Fatp1. Conversely, functional overexpression of FATP1 decreased many aspects of glucose metabolism and diminished CAM-stimulated inflammation in vitro. FATP1 displayed acyl-CoA synthetase activity for long chain fatty acids in MΦs and modulated lipid mediator metabolism in MΦs. CONCLUSION: Our findings provide evidence that FATP1 is a novel regulator of MΦ activation through control of substrate metabolism. Absence of FATP1 exacerbated pro-inflammatory activation in vitro and increased local and systemic components of the metabolic syndrome in HFD-fed Fatp1 (B-/-) mice. In contrast, gain of FATP1 activity in MΦs suggested that Fatp1-mediated activation of fatty acids, substrate switch to glucose, oxidative stress, and lipid mediator synthesis are potential mechanisms. We demonstrate for the first time that FATP1 provides a unique mechanism by which the inflammatory tone of adipose and systemic metabolism may be regulated.
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iNOS is an important metabolic regulator of the immune response because NO inhibits OXPHOS and oxidative metabolism, thus promoting the glycolytic and proinflammatory phenotype.
“iNOS is an important metabolic regulator of the immune response because NO inhibits OXPHOS and oxidative metabolism, thus promoting the glycolytic and proinflammatory phenotype (169, 170).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [169]
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- Authors
- Johnson, A. R., Qin, Y., Cozzo, A. J., Freemerman, A. J., Huang, M. J., Zhao, L., Sampey, B. P., Milner, J. J., Beck, M. A., Damania, B., Rashid, N., Galanko, J. A., Lee, D. P., Edin, M. L., Zeldin, D. C., Fueger, P. T., Dietz, B., Stahl, A., Wu, Y., Mohlke, K. L., & Makowski, L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- National Institutes of Health (US)
- Indiana University Indianapolis (US)
- University of California, Berkeley (US)
- Corresponding author
- Makowski, Liza
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 5
- Issue
- 7
- Pages
- 506-526
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC4921943
- OpenAlex
- W2345105372
- Cited by
- 130
- References
- 100
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 13 · 2023: 9 · 2022: 10 · 2021: 16 · 2020: 14 · 2019: 19 · 2018: 14 · 2017: 13 · 2016: 2
- FWCI
- 14.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (F32HL75970, P30DK056350, Z01ES025034, DK034987, DK099311, R01CA096500, DK089202, DK101293, AA017376)
- UNC undergraduate research fellowship
- Sanofi Global Scholar pre-doctoral fellowship
- UNC Chancellor's Fellowship
- American Heart Association (1-14-BS-191)
- UNC University Cancer Research
- Academy of Finland (124243)
- Finnish Heart Foundation
- Finnish Diabetes Foundation
- Tekes contract (1510/31/06)
- Commission of the European Community (HEALTH-F2-2007-201681)
- US NIH (DK093757, DK072193, DK062370, 1Z01 HG000024)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- bacteriophages, FATP1, metabolic reprogramming, adipose tissue inflammation, obesity, macrophage polarization, M1 macrophages, M2 macrophages, glucose metabolism, fatty acid metabolism, metabolic flexibility, insulin resistance, high-fat diet, oxidative stress, lipid trafficking, chimeric mice, RAW 264.7
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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