Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody

Abstract

Obesity dysregulates B cell populations, which contributes toward poor immunological outcomes. We previously reported that differing B cell subsets are lowered in the bone marrow of obese male mice. Here, we focused on how lipid metabolites synthesized from docosahexaenoic acid (DHA) known as specialized pro‐resolving lipid mediators (SPMs) influence specific B cell populations in obese male mice. Metabololipidomics revealed that splenic SPM precursors 14‐hydroxydocosahexaenoic acid (14‐HDHA), 17‐hydroxydocosahexaenoic acid (17‐HDHA), and downstream protectin DX (PDX) were decreased in obese male C57BL/6J mice. Simultaneous administration of these mediators to obese mice rescued major decrements in bone marrow B cells, modest impairments in the spleen, and circulating IgG2c, which is pro‐inflammatory in obesity. In vitro studies with B cells, flow cytometry experiments with ALOX5−/− mice, and lipidomic analyses revealed the lowering of 14‐HDHA/17‐HDHA/PDX and dysregulation of B cell populations in obesity was driven indirectly via B cell extrinsic mechanisms. Notably, the lowering of lipid mediators was associated with an increase in the abundance of n‐6 polyunsaturated fatty acids, which have a high affinity for SPM‐generating enzymes. Subsequent experiments revealed female obese mice generally maintained the levels of SPM precursors, B cell subsets, and antibody levels. Finally, obese human females had increased circulating plasma cells accompanied by ex vivo B cell TNFα and IL‐10 secretion. Collectively, the data demonstrate that DHA‐derived mediators of the SPM pathway control the number of B cell subsets and pro‐inflammatory antibody levels in obese male but not female mice through a defect that is extrinsic to B cells.

Interactive effects of maternal and weaning high linoleic acid intake on hepatic lipid metabolism, oxylipins profile and hepatic steatosis in offspring

“…We demonstrated that high LA intake decreased plasma levels of SPM precursors, 14-HDHA and 17-HDHA, and their downstream products MaR1 and PDX, known for their anti-inflammatory and pro-resolving properties. Our data are in lines with recent evidence showing that obesity was associated with a downregulation of EPA-and DHA-derived SPM [21,[67][68][69]. The authors have linked the n-3 derived…”

“…derivatives at the expense of n-3 PUFA derivatives as described in high fat diet studies [21,67]. We demonstrated that high LA intake decreased plasma levels of SPM precursors, 14-HDHA and 17-HDHA, and their downstream products MaR1 and PDX, known for their anti-inflammatory and pro-resolving properties.…”

Resolvin E1 derived from eicosapentaenoic acid prevents hyperinsulinemia and hyperglycemia in a host genetic manner

“…SPMs are synthesized predominately from the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) 1 . There is growing evidence from humans and mouse models that obesity impairs the biosynthesis of SPMs and their precursors [5][6][7][8] . The loss of SPMs contributes toward a range of obesity-related complications including chronic inflammation, hepatic steatosis, insulin resistance, susceptibility to infection, and delayed wound healing 6,[9][10][11][12][13][14] .…”

A Perspective and Framework for Developing Sample Type Specific Databases for LC/MS-Based Clinical Metabolomics

“…It should be noted that routinely used sample preparation and LC/MS methods will not allow for the detection of all compounds. We address this in our own lab by developing targeted methods for compounds (e.g., oxylipins, nucleotides [53,54]) that are not typically detected in our LC/MS profiling studies. The purpose of STSDBs is not to provide 100% coverage of a particular metabolome; rather, if a compound can be detected using standard methods, it will become part of an STSDB.…”