14-hydroxydocosahexaenoate and Obesity

Cardiovascular disease, a major cause of mortality and morbidity, exhibits sexual dimorphism since the onset of cardiovascular disease occurs later in women than in men. The loss of cardioprotection in older women may be due to an increase in arterial stiffness after menopause. Free fatty acid metabolites of polyunsaturated fatty acids, called oxylipins, are known to impact vessel function and may be responsible for the vascular benefits of polyunsaturated fatty acids. The objectives of this study were to compare the plasma oxylipin profiles of young females (20-55 years), older females (55. Higher 12-lipoxygenase oxylipin plasma concentrations associated with lower arterial stiffness in premenopausal females may be an important contributing factor to sex differences in cardiovascular disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01661543, NCT01562171, NCT01890330, NCT02571114 and NCT02317588.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Adult; Age Factors; Aged; Ankle Brachial Index; Biomarkers; Cardiovascular Diseases; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Health Status Disparities; Heart Disease Risk Factors; Humans; Male; Menopause; Middle Aged; Obesity; Oxylipins; Pulse Wave Analysis; Risk Assessment; Sex Factors; Up-Regulation; Vascular Stiffness; Young Adult

Topics: Animals; Antibodies; B-Lymphocyte Subsets; Biomarkers; Bone Marrow Cells; Diet, High-Fat; Disease Models, Animal; Disease Susceptibility; Docosahexaenoic Acids; Female; Germinal Center; Humans; Immunophenotyping; Inflammation Mediators; Lipid Metabolism; Lymphocyte Activation; Lymphocyte Count; Male; Metabolomics; Mice; Mice, Knockout; Mice, Obese; Obesity; Phenotype; Sex Factors

Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished Ab titers whereas the Western diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.

Topics: Animals; B-Lymphocytes; Diet, Western; Disease Models, Animal; Docosahexaenoic Acids; Fatty Acids, Essential; Humans; Immunity, Humoral; Immunoglobulin M; Influenza A virus; Interleukin-6; Lymphocyte Activation; Mice; Obesity; Orthomyxoviridae Infections; Toll-Like Receptor 9

White adipose tissue (WAT) is a complex organ with both metabolic and endocrine functions. Dysregulation of all of these functions of WAT, together with low-grade inflammation of the tissue in obese individuals, contributes to the development of insulin resistance and type 2 diabetes. n-3 polyunsaturated fatty acids (PUFAs) of marine origin play an important role in the resolution of inflammation and exert beneficial metabolic effects. Using experiments in mice and overweight/obese patients with type 2 diabetes, we elucidated the structures of novel members of fatty acid esters of hydroxy fatty acids-lipokines derived from docosahexaenoic acid (DHA) and linoleic acid, which were present in serum and WAT after n-3 PUFA supplementation. These compounds contained DHA esterified to 9- and 13-hydroxyoctadecadienoic acid (HLA) or 14-hydroxydocosahexaenoic acid (HDHA), termed 9-DHAHLA, 13-DHAHLA, and 14-DHAHDHA, and were synthesized by adipocytes at concentrations comparable to those of protectins and resolvins derived from DHA in WAT. 13-DHAHLA exerted anti-inflammatory and proresolving properties while reducing macrophage activation by lipopolysaccharides and enhancing the phagocytosis of zymosan particles. Our results document the existence of novel lipid mediators, which are involved in the beneficial anti-inflammatory effects attributed to n-3 PUFAs, in both mice and humans.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue, White; Animals; Anti-Inflammatory Agents; Cells, Cultured; Diabetes Mellitus, Type 2; Docosahexaenoic Acids; Esters; Fatty Acids, Unsaturated; Humans; Inflammation; Insulin Resistance; Linoleic Acid; Lipopolysaccharides; Macrophage Activation; Male; Mice; Mice, Inbred C57BL; Obesity; Phagocytosis