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Resolvin E1 (RvE1), a specialized pro-resolving mediator (SPM), improves glucose homeostasis in inbred mouse models of obesity. However, an impediment toward translation is that obesity is a highly heterogenous disease in which individuals will respond very differently to interventions such as RvE1. Thus, there is a need to study SPMs in the context of modeling the heterogeneity of obesity that is observed in humans. We investigated how RvE1 controls the concentration of key circulating metabolic biomarkers using diversity outbred (DO) mice, which mimic human heterogeneity. We first demonstrate that weights of DO mice can be classified into distinct distributions of fat mass (i.e., modeling differing classes of obesity) in response to a high-fat diet and in the human population when examining body composition. Next, we show RvE1 administration based on body weight for four consecutive days after giving mice a high-fat diet led to approximately half of the mice responding positively for serum total gastric inhibitory polypeptide (GIP), glucagon, insulin, glucose, leptin, and resistin. Interestingly, RvE1 improved hyperleptinemia most effectively in the lowest class of fat mass despite adjusting the dose of RvE1 with increasing adiposity. Furthermore, leptin levels after RvE1 treatment were the lowest in those mice that were also RvE1 positive responders for insulin and resistin. Collectively, these results suggest a therapeutic fat mass-dependent window for RvE1, which should be considered in future clinical trials. Moreover, the data underscore the importance of studying SPMs with heterogenous mice as a step toward precision SPM administration in humans., (© 2022 Federation of American Societies for Experimental Biology.)

Obesity is an independent risk factor for morbidity and mortality in response to influenza infection. However, the underlying mechanisms by which obesity impairs immunity are unclear. Herein, we investigated the effects of diet-induced obesity on pulmonary CD8 + T cell metabolism, cytokine production, and transcriptome as a potential mechanism of impairment during influenza virus infection in mice. Male C57BL/6J lean and obese mice were infected with sub-lethal mouse-adapted A/PR/8/34 influenza virus, generating a pulmonary anti-viral and inflammatory response. Extracellular metabolic flux analyses revealed pulmonary CD8 + T cells from obese mice, compared with lean controls, had suppressed oxidative and glycolytic metabolism at day 10 post-infection. Flow cytometry showed the impairment in pulmonary CD8 + T cell metabolism with obesity was independent of changes in glucose or fatty acid uptake, but concomitant with decreased CD8 + GrB + IFNγ + populations. Notably, the percent of pulmonary effector CD8 + GrB + IFNγ + T cells at day 10 post-infection correlated positively with total CD8 + basal extracellular acidification rate and basal oxygen consumption rate. Finally, next-generation RNA sequencing revealed complex and unique transcriptional regulation of sorted effector pulmonary CD8 + CD44 + T cells from obese mice compared to lean mice following influenza infection. Collectively, the data suggest diet-induced obesity increases influenza virus pathogenesis, in part, through CD8 + T cell-mediated metabolic reprogramming and impaired effector CD8 + T cell function., (©2021 Society for Leukocyte Biology.)

Obesity drives an imbalanced signature of specialized pro-resolving mediators (SPM). Herein, we investigated if high fat diet-induced obesity dysregulates the concentration of SPM intermediates in the brains of C57BL/6 J mice. Furthermore, given the benefits of EPA for cardiometabolic diseases, major depression, and cognition, we probed the effect of an EPA supplemented high fat diet on brain SPM intermediates. Mass spectrometry revealed no effect of the high fat diet on PUFA-derived brain metabolites. EPA also did not have an effect on most brain PUFA-derived metabolites except an increase of 12-hydroxyeicosapentaenoic acid (12-HEPE). In contrast, EPA dramatically increased serum HEPEs and lowered several PUFA-derived metabolites. Finally, untargeted mass spectrometry showed no effects of the high fat diet, with or without EPA, on the brain metabolome. Collectively, these results show the murine brain resists a deficiency in SPM pathway markers in response to a high fat diet and that EPA supplementation increases 12-HEPE levels., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Obesity is routinely considered as a single disease state, which drives a "one-size-fits-all" approach to treatment. We recently convened the first annual University of North Carolina Interdisciplinary Nutrition Sciences Symposium to discuss the heterogeneity of obesity and the need for translational science to advance understanding of this heterogeneity. The symposium aimed to advance scientific rigor in translational studies from animal to human models with the goal of identifying underlying mechanisms and treatments. In this review, we discuss fundamental gaps in knowledge of the heterogeneity of obesity ranging from cellular to population perspectives. We also advocate approaches to overcoming limitations in the field. Examples include the use of contemporary mouse genetic reference population models such as the Collaborative Cross and Diversity Outbred mice that effectively model human genetic diversity and the use of translational models that integrate -omics and computational approaches from pre-clinical to clinical models of obesity. Finally, we suggest best scientific practices to ensure strong rigor that will allow investigators to delineate the sources of heterogeneity in the population with obesity. Collectively, we propose that it is critical to think of obesity as a heterogeneous disease with complex mechanisms and etiologies, requiring unique prevention and treatment strategies tailored to the individual., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Diet-induced obesity is associated with impaired B-cell-driven humoral immunity, which coincides with chronic inflammation and has consequences for responses to infections and vaccinations. Key nutritional, cellular, and molecular mechanisms by which obesity may impair aspects of humoral immunity such as B cell development, class switch recombination, and formation of long-lived antibody secreting cells are reviewed. A key theme to emerge is the central role of white adipose tissue on the formation and function of pro-inflammatory B cell subsets that exacerbate insulin resistance. The underlying role of select hormones such as leptin is highlighted, which may be driving the formation of pro-inflammatory B cells in the absence of antigen stimulation. This review also extensively covers the regulatory role of lipid metabolites such as prostaglandins and specialized pro-resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. Notably, SPM biosynthesis is impaired in obesity and contributes toward impaired antibody production. Future directions for research, including avenues for therapeutic intervention, are included., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Obesity is a major independent risk factor for increased morbidity and mortality upon infection with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), which is responsible for the current coronavirus disease pandemic (COVID-19). Therefore, there is a critical need to identify underlying metabolic factors associated with obesity that could be contributing toward increased susceptibility to SARS-CoV-2 in this vulnerable population. Here, we focus on the critical role of potent endogenous lipid metabolites known as specialized pro-resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. SPMs are generated during the transition of inflammation to resolution and have a vital role in directing damaged tissues to homeostasis; furthermore, SPMs display anti-viral activity in the context of influenza infection without being immunosuppressive. We cover evidence from rodent and human studies to show that obesity, and its co-morbidities, induce a signature of SPM deficiency across immunometabolic tissues. We further discuss how the effects of obesity upon SARS-CoV-2 infection are likely exacerbated with environmental exposures that promote chronic pulmonary inflammation and augment SPM deficits. Finally, we highlight potential approaches to overcome the loss of SPMs using dietary and pharmacological interventions. Collectively, this mini-review underscores the need for mechanistic studies on how SPM deficiencies driven by obesity and environmental exposures may exacerbate the response to SARS-CoV-2., (Copyright © 2020 Pal, Gowdy, Oestreich, Beck and Shaikh.)

Chronic unresolved inflammation is the primary determinant of cardiovascular disease. Precise mechanisms that define the genesis of unresolved inflammation in heart failure with preserved ejection fraction (HFpEF) are of interest due to the obesity epidemic. To examine the obesity phenotype and its direct/indirect consequences, multiple approaches were employed using the lipoxin receptor (abbreviated as ALX) dysfunction mouse model. Indirect calorimetry analyses revealed that the deletion of ALX dysregulated energy metabolism driving toward age-related obesity. Heart function data suggest that obesity-prone ALX deficient mice had impaired myocardium strain. Comprehensive measurement of chemokines, extracellular matrix, and arrhythmogenic arrays confirmed the dysregulation of multiple ion channels gene expression with amplified inflammatory chemokines and cytokines response at the age of 4 months compared with WT counterparts. Quantitative analyses of leukocytes demonstrated an increase of proinflammatory Ly6C hi CCR2 + macrophages in the spleen and heart at a steady-state resulting in an inflamed splenocardiac axis. Signs of subtle inflammation were marked with cardiorenal, endothelial defects with decreased CD31 and eNOS and an increased iNOS and COX2 expression. Thus, ALX receptor deficiency serves as an experimental model that defines multiple cellular and molecular mechanisms in HFpEF that could be a target for the development of HFpEF therapy in cardiovascular medicine., (© 2020 Federation of American Societies for Experimental Biology.)

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., (©2018 Society for Leukocyte Biology.)

The long-chain n-3 polyunsaturated fatty acids (LC-PUFAs) eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) in fish oil have immunomodulatory properties. B cells are a poorly studied target of EPA/DHA in humans. Therefore, in this pilot study, we tested how n-3 LC-PUFAs influence B-cell responses of obese humans. Obese men and women were assigned to consume four 1-g capsules per day of olive oil (OO, n=12), fish oil (FO, n=12) concentrate or high-DHA-FO concentrate (n=10) for 12 weeks in a parallel design. Relative to baseline, FO (n=9) lowered the percentage of circulating memory and plasma B cells, whereas the other supplements had no effect. There were no postintervention differences between the three supplements. Next, ex vivo B-cell cytokines were assayed after stimulation of Toll-like receptors (TLRs) and/or the B-cell receptor (BCR) to determine if the effects of n-3 LC-PUFAs were pathway-dependent. B-cell IL-10 and TNFα secretion was respectively increased with high DHA-FO (n=10), relative to baseline, with respective TLR9 and TLR9+BCR stimulation. OO (n=12) and FO (n=12) had no influence on B-cell cytokines compared to baseline, and there were no differences in postintervention cytokine levels between treatment groups. Finally, ex vivo antibody levels were assayed with FO (n=7) after TLR9+BCR stimulation. Compared to baseline, FO lowered IgM but not IgG levels accompanied by select modifications to the plasma lipidome. Altogether, the results suggest that n-3 LC-PUFAs could modulate B-cell activity in humans, which will require further testing in a larger cohort., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 by The American Association of Immunologists, Inc.)

EPA and DHA are not biologically equivalent; however, their individual activity on B cells is unknown. We previously reported fish oil enhanced murine B-cell activity in obesity. To distinguish between the effects of EPA and DHA, we studied the ethyl esters of EPA and DHA on murine B-cell function as a function of time. We first demonstrate that EPA and DHA maintained the obese phenotype, with no improvements in fat mass, adipose inflammatory cytokines, fasting insulin, or glucose clearance. We then tested the hypothesis that EPA and DHA would increase the frequency of splenic B cells. EPA and DHA differentially enhanced the frequency and/or percentage of select B-cell subsets, correlating with increased natural serum IgM and cecal IgA. We next determined the activities of EPA and DHA on ex vivo production of cytokines upon lipopolysaccharide stimulation of B cells. EPA and DHA, in a time-dependent manner, enhanced B-cell cytokines with DHA notably increasing IL-10. At the molecular level, EPA and DHA differentially enhanced the formation of ordered microdomains but had no effect on Toll-like receptor 4 mobility. Overall, the results establish differential effects of EPA and DHA in a time-dependent manner on B-cell activity in obesity, which has implications for future clinical studies., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

The role of n-3 polyunsaturated fatty acids (PUFA) on in vivo B-cell immunity is unknown. We first investigated how n-3 PUFAs impacted in vivo B-cell phenotypes and antibody production in the absence and presence of antigen compared with a control diet. Lean mice consuming n-3 PUFAs for 4 weeks displayed increased percentage and frequency of splenic transitional 1 B cells. Upon stimulation with trinitrophenylated-lipopolysaccharide, n-3 PUFAs increased the number of splenic transitional 1/2, follicular, premarginal, and marginal zone B cells. n-3 PUFAs also increased surface, but not circulating, IgM. We next tested the effects of n-3 PUFAs in a model of obesity that is associated with suppressed humoral immunity. An obesogenic diet after ten weeks of feeding, relative to a lean control, had no effect on the frequency of B cells but lowered circulating IgM upon antigen stimulation. Administration of n-3 PUFAs to lean and obese mice increased the percentage and/or frequency of transitional 1 and marginal zone B cells. Furthermore, n-3 PUFAs in lean and obese mice increased circulating IgM relative to controls. Altogether, the data show n-3 PUFAs enhance B cell-mediated immunity in vivo, which has implications for immunocompromised populations, such as the obese.

Obesity is associated with a wide range of complications, including type 2 diabetes mellitus, cardiovascular disease, hypertension and nonalcoholic fatty liver disease. Obesity also increases the incidence and progression of cancers, autoimmunity and infections, as well as lowering vaccine responsiveness. A unifying concept across these differing diseases is dysregulated immunity, particularly inflammation, in response to metabolic overload. Herein, we review emerging mechanisms by which obesity drives inflammation and autoimmunity, as well as impairing tumour immunosurveillance and the response to infections. Among these mechanisms are obesity-associated changes in the hormones that regulate immune cell metabolism and function and drive inflammation. The cargo of extracellular vesicles derived from adipose tissue, which controls cytokine secretion from immune cells, is also dysregulated in obesity, in addition to impairments in fatty acid metabolism related to inflammation. Furthermore, an imbalance exists in obesity in the biosynthesis and levels of polyunsaturated fatty acid-derived oxylipins, which control a range of outcomes related to inflammation, such as immune cell chemotaxis and cytokine production. Finally, there is a need to investigate how obesity influences immunity using innovative model systems that account for the heterogeneous nature of obesity in the human population. In this Review, the emerging cellular and molecular mechanisms by which obesity impairs key aspects of immunity are discussed, including changes in the abundance of key hormones, dysregulation of adipose-tissue-derived extracellular vesicles and dysregulation of polyunsaturated fatty acid metabolism. Key points: Obesity dysregulates immunity through differing mechanisms, which contribute to a range of secondary complications. Obesity influences the level and function of nutritionally regulated hormones that regulate signalling pathways that mediate immune cell metabolism and function and drive inflammation. Expansion of adipose tissue dysregulates the abundance and composition of extracellular vesicles, which carry a wide range of cargo that can affect the activity of immune cells and lipid metabolism. Increased adiposity dysregulates polyunsaturated fatty acid metabolism; notably, the concentration of oxylipins synthesized from polyunsaturated fatty acids, which control a range of outcomes related to inflammation, is imbalanced in obesity. Investigating immunity in obesity requires translation from inbred rodents to humans; one approach is to use Diverse Outbred and Collaborative Cross mouse populations that can model the heterogeneous nature of human obesity. [ABSTRACT FROM AUTHOR]

Diet-induced obesity impairs mitochondrial respiratory responses in tissues that are highly metabolically active, such as the heart. However, less is known about the impact of obesity on the respiratory activity of specific cell types, such as splenic B cells. B cells are of relevance, as they play functional roles in obesity-induced insulin resistance, inflammation, and responses to infection. Here, we tested the hypothesis that high-fat-diet (HFD)-induced obesity could impair the mitochondrial respiration of intact and permeabilized splenic CD19+ B cells isolated from C57BL/6J mice and activated ex vivo with lipopolysaccharide (LPS). High-resolution respirometry was used with intact and permeabilized cells. To reveal potential mechanistic targets by which HFD-induced obesity dysregulates B cell mitochondria, we conducted proteomic analyses and 3D serial block face scanning electron microscopy (SBFEM). High-resolution respirometry revealed that intact LPS-stimulated B cells of obese mice, relative to controls, displayed lower ATP-linked, as well as maximal uncoupled, respiration. To directly investigate mitochondrial function, we used permeabilized LPS-stimulated B cells, which displayed increased H2O2 emission and production with obesity. We also examined oxidative phosphorylation efficiency simultaneously, which revealed that oxygen consumption and ATP production were decreased in LPS-stimulated B cells with obesity relative to controls. Despite minimal changes in total respiratory complex abundance, in LPS-stimulated B cells of obese mice, three of the top ten most downregulated proteins were all accessory subunits of respiratory complex I. SBFEM showed that B cells of obese mice, compared to controls, underwent no change in mitochondrial cristae integrity but displayed increased mitochondrial volume that was linked to bioenergetic function. Collectively, these results establish a proof of concept that HFD-induced obesity dysregulates the mitochondrial bioenergetic metabolism of activated splenic B cells. [ABSTRACT FROM AUTHOR]

Background Obesity dysregulates immunity to influenza infection. Therefore, there is a critical need to investigate how obesity impairs immunity and to establish therapeutic approaches that mitigate the impact of increased adiposity. One mechanism by which obesity may alter immune responses is through changes in cellular metabolism. Methods We studied inflammation and cellular metabolism of peripheral blood mononuclear cells (PBMCs) isolated from individuals with obesity relative to lean controls. We also investigated if impairments to PBMC metabolism were reversible upon short-term weight loss following bariatric surgery. Results Obesity was associated with systemic inflammation and poor inflammation resolution. Unstimulated PBMCs from participants with obesity had lower oxidative metabolism and adenosine triphosphate (ATP) production compared to PBMCs from lean controls. PBMC secretome analyses showed that ex vivo stimulation with A/Cal/7/2009 H1N1 influenza led to a notable increase in IL-6 with obesity. Short-term weight loss via bariatric surgery improved biomarkers of systemic metabolism but did not improve markers of inflammation resolution, PBMC metabolism, or the PBMC secretome. Conclusions These results show that obesity drives a signature of impaired PBMC metabolism, which may be due to persistent inflammation. PBMC metabolism was not reversed after short-term weight loss despite improvements in measures of systemic metabolism. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic demonstrates that obesity alone, independent of comorbidities, is a significant risk factor for severe outcomes from infection. This susceptibility mirrors a similar pattern with influenza infection; that is, obesity is a unique risk factor for increased morbidity and mortality. Therefore, it is critical to understand how obesity contributes to a reduced ability to respond to respiratory viral infections. Herein, we discuss human and animal studies with influenza infection and vaccination that show obesity impairs immunity. We cover several key mechanisms for the dysfunction. These mechanisms include systemic and cellular level changes that dysregulate immune cell metabolism and function in addition to how obesity promotes deficiencies in metabolites that control the resolution of inflammation and infection. Finally, we discuss major gaps in knowledge, particularly as they pertain to diet and mechanisms, which will drive future efforts to improve outcomes in response to respiratory viral infections in an increasingly obese population. [ABSTRACT FROM AUTHOR]

Background: Specialized pro-resolving mediators (SPMs), synthesized from PUFAs, resolve inflammation and return damaged tissue to homeostasis. Thus, increasing metabolites of the SPM biosynthetic pathway may have potential health benefits for select clinical populations, such as subjects with obesity who display dysregulation of SPM metabolism. However, the concentrations of SPMs and their metabolic intermediates in humans with obesity remains unclear.Objectives: The primary objective of this study was to determine if a marine oil supplement increased specific metabolites of the SPM biosynthetic pathway in adults with obesity. The second objective was to determine if the supplement changed the relative abundance of key immune cell populations. Finally, given the critical role of antibodies in inflammation, we determined if ex vivo CD19 + B-cell antibody production was modified by marine oil intervention.Methods: Twenty-three subjects [median age: 56 y; BMI (in kg/m2): 33.1] consumed 2 g/d of a marine oil supplement for 28-30 d. The supplement was particularly enriched with 18-hydroxyeicosapentaenoic (HEPE), 14-hydroxydocosahexaenoic acid (14-HDHA), and 17-HDHA. Blood was collected pre- and postsupplementation for plasma mass spectrometry oxylipin and fatty acid analyses, flow cytometry, and B-cell isolation. Paired t-tests and Wilcoxon tests were used for statistical analyses.Results: Relative to preintervention, the supplement increased 6 different HEPEs and HDHAs accompanied by changes in plasma PUFAs. Resolvin E1 and docosapentaenoic acid-derived maresin 1 concentrations were increased 3.5- and 4.7-fold upon intervention, respectively. The supplement did not increase the concentration of D-series resolvins and had no effect on the abundance of immune cells. Ex vivo B-cell IgG but not IgM concentrations were lowered postsupplementation.Conclusions: A marine oil supplement increased select SPMs and their metabolic intermediates in adults with obesity. Additional studies are needed to determine if increased concentrations of specific SPMs control the resolution of inflammation in humans with obesity. This trial was registered at clinicaltrials.gov as NCT04701138. [ABSTRACT FROM AUTHOR]

Obesity is an independent risk factor for morbidity and mortality in response to influenza infection. However, the underlying mechanisms by which obesity impairs immunity are unclear. Herein, we investigated the effects of diet‐induced obesity on pulmonary CD8+ T cell metabolism, cytokine production, and transcriptome as a potential mechanism of impairment during influenza virus infection in mice. Male C57BL/6J lean and obese mice were infected with sub‐lethal mouse‐adapted A/PR/8/34 influenza virus, generating a pulmonary anti‐viral and inflammatory response. Extracellular metabolic flux analyses revealed pulmonary CD8+ T cells from obese mice, compared with lean controls, had suppressed oxidative and glycolytic metabolism at day 10 post‐infection. Flow cytometry showed the impairment in pulmonary CD8+ T cell metabolism with obesity was independent of changes in glucose or fatty acid uptake, but concomitant with decreased CD8+GrB+IFNγ+ populations. Notably, the percent of pulmonary effector CD8+GrB+IFNγ+ T cells at day 10 post‐infection correlated positively with total CD8+ basal extracellular acidification rate and basal oxygen consumption rate. Finally, next‐generation RNA sequencing revealed complex and unique transcriptional regulation of sorted effector pulmonary CD8+CD44+ T cells from obese mice compared to lean mice following influenza infection. Collectively, the data suggest diet‐induced obesity increases influenza virus pathogenesis, in part, through CD8+ T cell‐mediated metabolic reprogramming and impaired effector CD8+ T cell function. [ABSTRACT FROM AUTHOR]

Chronic inflammation contributes toward the pathogenesis of numerous diseases including, but not limited to, obesity, autoimmunity, cardiovascular diseases, and cancers. The discovery of specialized pro-resolving mediators (SPMs), which are critical for resolving inflammation, has commenced investigation into targeting pathways of inflammation resolution to improve physiological outcomes. SPMs are predominately synthesized from the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Therefore, one viable strategy to promote inflammation resolution would be to increase dietary intake of EPA/DHA, which are deficient in select populations. However, there are inconsistencies between the use of EPA/DHA as dietary or pharmacological supplements and improved inflammatory status. Herein, we review the literature on the relationship between the high n-6/n-3 PUFA ratio, downstream SPM biosynthesis, and inflammatory endpoints. We highlight key studies that have investigated how dietary intake of EPA/DHA increase tissue SPMs and their effects on inflammation. We also discuss the biochemical pathways by which EPA/DHA drive SPM biosynthesis and underscore mechanistic gaps in knowledge about these pathways which include a neglect for host genetics/ethnic differences in SPM metabolism, sexual dimorphism in SPM levels, and potential competition from select dietary n-6 PUFAs for enzymes of SPM synthesis. Altogether, establishing how dietary PUFAs control SPM biosynthesis in a genetic- and sex-dependent manner will drive new precision nutrition studies with EPA/DHA to prevent chronic inflammation in select populations. • The western diet is generally low in long chain n-3 PUFAs. • Low dietary n-3 PUFAs may contribute to a pro-inflammatory profile. • PUFA-derived SPM levels are unbalanced in chronic inflammatory diseases. • SNPs in enzymes of SPM biosynthesis may have direct clinical translation. • Establishing genetic differences in SPM metabolism will drive precision studies. [ABSTRACT FROM AUTHOR]

Cardiac phospholipids, notably cardiolipin, undergo acyl chain remodeling and/or loss of content in aging and cardiovascular diseases, which is postulated to mechanistically impair mitochondrial function. Less is known about how diet-induced obesity influences cardiac phospholipid acyl chain composition and thus mitochondrial responses. Here we first tested if a high fat diet remodeled murine cardiac mitochondrial phospholipid acyl chain composition and consequently disrupted membrane packing, supercomplex formation and respiratory enzyme activity. Mass spectrometry analyses revealed that mice consuming a high fat diet displayed 0.8-3.3 fold changes in cardiac acyl chain remodeling of cardiolipin, phosphatidylcholine, and phosphatidylethanolamine. Biophysical analysis of monolayers constructed from mitochondrial phospholipids of obese mice showed impairment in the packing properties of the membrane compared to lean mice. However, the high fat diet, relative to the lean controls, had no influence on cardiac mitochondrial supercomplex formation, respiratory enzyme activity, and even respiration. To determine if the effects were tissue specific, we subsequently conducted select studies with liver tissue. Compared to the control diet, the high fat diet remodeled liver mitochondrial phospholipid acyl chain composition by 0.6-5.3-fold with notable increases in n-6 and n-3 polyunsaturation. The remodeling in the liver was accompanied by diminished complex I to III respiratory enzyme activity by 3.5-fold. Finally, qRT-PCR analyses demonstrated an upregulation of liver mRNA levels of tafazzin, which contributes to cardiolipin remodeling. Altogether, these results demonstrate that diet-induced obesity remodels acyl chains in the mitochondrial phospholipidome and exerts tissue specific impairments of respiratory enzyme activity. [ABSTRACT FROM AUTHOR]