Journal
FASEB JOURNAL
Volume 33, Issue 6, Pages 7072-7083Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201802587R
Keywords
specialized proresolving mediator; lipoxygenases; obesity
Categories
Funding
- Spanish Ministerio de Economia y Competitividad (MEC) under the European Regional Development Fund (ERDF) [SAF15/63674-R, PIE14/00045]
- Instituto de Salud Carlos III
- Generalitat de Catalunya [2017SGR1449]
- European Research Council (ERC) under the European Union [677542]
- Barts Charity [MGU0343]
- Sir Henry Dale Fellowship - Wellcome Trust [107613/Z/15/Z]
- Sir Henry Dale Fellowship - Royal Society [107613/Z/15/Z]
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Specialized proresolving mediators (SPMs) biosynthesized from docosahexaenoic acids (DHAs) including resolvins (Rvs), protectins, and maresins are potent endogenous autacoids that actively resolve inflammation, protect organs, and stimulate tissue regeneration. Our hypothesis was that failure of resolution programs may lead to unremitting inflammation in obesity, contributing to the development of metabolic comorbidities in this condition. Obese individuals with persistent low-grade systemic inflammation showed reduced leukocyte production of the DHA-derived monohydroxy fatty acid 17-hydroxy-DHA (HDHA) and unbalanced formation of SPMs (in particular D-series Rvs) accompanied by enhanced production of proinflammatory lipid mediators such as leukotriene B-4. Mechanistic studies attributed this impairment to reduced 15-lipoxygenase (LOX) activity rather than altered DHA cellular uptake. Moreover, leukocytes from obese individuals exhibited decreased 5-LOX levels and reduced 5-LOX Ser271 phosphorylation and distinct intracellular 5-LOX redistribution. However, 15-LOX appears to be the most critical factor for the deficient production of SPMs by obese leukocytes because the formation of D-series Rvs was completely rescued by incubation with the intermediate precursor 17-HDHA. These data provide proof of concept that administration of intermediate precursors of SPM biosynthesis (e.g., 17-HDHA) could be more efficient in overriding impaired formation of these proresolving lipid mediators in conditions characterized by dysfunctional LOX activity, such as obesity.-Lopez-Vicario, C., Titos, E., Walker, M. E., Alcaraz-Quiles, J., Casulleras, M., Duran-Guell, M., Flores-Costa, R., Perez-Romero, N., Forne, M., Dalli, J., Claria, J. Leukocytes from obese individuals exhibit an impaired SPM signature.
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