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Abstract

Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation. However, glycolysis was not critical for Th17 cytokines. Instead, β oxidation blockade or CACT knockdown in T cells from lean subjects to mimic characteristics of T2D causes cells to utilize 16C-fatty acylcarnitine to support Th17 cytokines. These data show long-chain acylcarnitine combines with compromised β oxidation to promote disease-predictive inflammation in human T2D.

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... Since that time, insight into the degree and specificity of obesity's effects on particular immune populations has grown rapidly. Obesity-induced alterations in the composition, activity, metabolism, and effector response of the immune system have lent much needed insight into the potential mechanisms by which obesity alters disease severity, progression, and response to therapies for immune-mediated pathologies (35)(36)(37)(38)(39)(40). Because MSC therapy relies on paracrine activity and cell-to-cell interactions (41,42), significant questions remain regarding whether MSCs can appropriately function within this environment. ...
... Within the visceral adipose of patients with metabolic disease, Th1 numbers and function are increased, which is integral to initiation and maintenance of meta-inflammation (31,154). Additionally, both adults and children with obesity have elevations in Th17 cytokines, which is associated with T2DM and an IL-17 mediated disturbance of insulin signalling (35,38,155,156). This increased Th17 cytokine production appears to be linked to obesity-associated mitochondrial dysfunction in T cells (157). ...
... In obesity and metabolic disease, monocytes and macrophages are integral players in the initiation and sustained inflammation that drives systemic and adiposespecific physiological alterations (32,33,(38)(39)(40)198). A number of intrinsic features of monocytes and macrophages are compromised in patients living with obesity. ...
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Mesenchymal stromal cell (MSC) therapy has seen increased attention as a possible option to treat a number of inflammatory conditions including COVID-19 acute respiratory distress syndrome (ARDS). As rates of obesity and metabolic disease continue to rise worldwide, increasing proportions of patients treated with MSC therapy will be living with obesity. The obese environment poses critical challenges for immunomodulatory therapies that should be accounted for during development and testing of MSCs. In this review, we look to cancer immunotherapy as a model for the challenges MSCs may face in obese environments. We then outline current evidence that obesity alters MSC immunomodulatory function, drastically modifies the host immune system, and therefore reshapes interactions between MSCs and immune cells. Finally, we argue that obese environments may alter essential features of allogeneic MSCs and offer potential strategies for licensing of MSCs to enhance their efficacy in the obese microenvironment. Our aim is to combine insights from basic research in MSC biology and clinical trials to inform new strategies to ensure MSC therapy is effective for a broad range of patients.
... Several studies have demonstrated that T2DM is associated with increased activation of T cells together with an activation of inflammatory pathways [39][40][41][42]. Low-grade chronic inflammation among patients with either T1DM or T2DM has been well recognized [39][40][41][42]. ...
... Several studies have demonstrated that T2DM is associated with increased activation of T cells together with an activation of inflammatory pathways [39][40][41][42]. Low-grade chronic inflammation among patients with either T1DM or T2DM has been well recognized [39][40][41][42]. CD8 T cells are indispensable for the adaptive immune response against infections due to the secretion of pro-inflammatory cytokines, such as IFN-γ and Tumor-Necrosis Factor-α (TNFα). ...
... CD4 T cells are also crucial, for the suppression and/or regulation of immune reaction by the production of various T cells cytokines. T cells have been reported to be deferentially distributed in individuals with T2DM [39][40][41][42]. Bouayad et al have documented that Th17, a subset of the CD4 T cells, and IL-17A levels are elevated in individuals with newly diagnosed T2DM, a finding, which is probably associated with chronic inflammation [39]. ...
Article
Introduction Currently, diabetes mellitus (DM) as well as coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are major public health issues worldwide. Background It has been suggested that patients with DM are more vulnerable to SARS-CoV-2 infection and suffer from more severe forms of the disease. Methods A literature search was performed using PubMed, Scopus and Google search engines. Results Angiotensin converting enzyme-2 (ACE2) is the major receptor of SARS-CoV-2 in the human host. The differential expression of ACE2 in the lungs of patients with DM makes them more susceptible to COVID-19. Additionally, acute or chronic hyperglycemia renders individuals in an immune-suppressive state, with impaired innate and adaptive immunity function, contributing also to the severity of COVID-19 infection among patients with DM. Other factors contributing to a more severe course of COVID-19 include the co-existence of obesity in T2DM; the endothelial inflammation induced by the SARS-CoV-2 infection, which aggravates the endothelial dysfunction observed in both T1DM and T2DM; and the hypercoagulability presented in COVID-19 infection that increases the thrombotic tendency in DM. Conclusion This review summarizes the pathophysiologic mechanisms underlying the co-existence of both pandemics as well as the current recommendations and future perspectives regarding optimal treatment of inpatients and outpatients with DM in the era of SARS-CoV-2 infection. Notably, the current recommended drugs for the treatment of severe COVID-19, dexamethasone and remdesivir, may cause hyperglycemia, an adverse effect that physicians should bear in mind, when caring for patients with DM and COVID-19.
... DM is a well-established risk factor for COVID-19 (2,17); however, the underlying mechanisms are unclear. In susceptible individuals, SARS-CoV-2 infection is thought to trigger a prolonged hyperinflammatory response, dubbed the cytokine storm (4,(18)(19)(20)(21)(22). DM, as a chronic inflammatory condition, may predispose individuals to a heightened inflammatory response (23,24). Mitochondrial disruption, rather than changes to glucose metabolism, has been found to lead to altered T-cell cytokine production (notably by Thelper 17 cells) in type 2 DM (23). ...
... Blood suPAR levels are notably high in individuals with type 1 or type 2 DM, even in the nonacute setting, and are strongly predictive of DM-related outcomes, such as nephropathy and atherosclerotic events (28,32,33). Several studies have identified a correlation between T-helper 17 cells and suPAR levels (34, 35), which may explain the predilection for individuals with DM to have higher suPAR levels (23,36). SuPAR differs from other biomarkers of inflammation in that it is not an acute-phase reactant: Levels remain stable in highly proinflammatory situations, such as acute myocardial infarction or cardiac surgery (27). ...
Article
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OBJECTIVE Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.
... T h 17 cells have unique glycolysis and lipogenesis metabolic profiles that drives differentiation and cytokine production (184). The significant alterations in lipolysis and lipogenesis in patients with T2DM impacts T h 17 function and suggests that despite the normalisation of blood glucose levels in T2DM, this might not be sufficient to reverse obesityassociated T-cell inflammation (185). ...
... It is not yet known whether susceptibility to severe COVID-19 symptoms align with certain diabetes subpopulations on account of their B-cell function or whether these subtleties are overwhelmed by other contributory factors like age, glycaemic control, ethnic origin or BMI. Patients with T1DM have a dysregulated T reg response and patients with T2DM have an aberrantly active T h 17 response, both of which lead to a sustained increase in proinflammatory cytokines (180,182,183,185). The increased proinflammatory cytokine profile already present in T1DM and T2DM could therefore skew the immune response to SARS-CoV-2 infection toward an inflammatory response, increasing the likelihood of severe COVID-19, with associated cytokine storm, tissue damage, and respiratory failure. ...
Article
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Meta-analyses have indicated that individuals with type 1 or type 2 diabetes are at increased risk of suffering a severe form of COVID-19 and have a higher mortality rate than the non-diabetic population. Patients with diabetes have chronic, low-level systemic inflammation, which results in global cellular dysfunction underlying the wide variety of symptoms associated with the disease, including an increased risk of respiratory infection. While the increased severity of COVID-19 amongst patients with diabetes is not yet fully understood, the common features associated with both diseases are dysregulated immune and inflammatory responses. An additional key player in COVID-19 is the enzyme, angiotensin-converting enzyme 2 (ACE2), which is essential for adhesion and uptake of virus into cells prior to replication. Changes to the expression of ACE2 in diabetes have been documented, but they vary across different organs and the importance of such changes on COVID-19 severity are still under investigation. This review will examine and summarise existing data on how immune and inflammatory processes interplay with the pathogenesis of COVID-19, with a particular focus on the impacts that diabetes, endothelial dysfunction and the expression dynamics of ACE2 have on the disease severity.
... August 2021 | Volume 2 | Article 681428 correlation between the number of medications people were on and the number of CD8 + EMRA T cells. Furthermore, we found no effect of metformin usage on CD8 + EMRA T cells, a finding that is supported by work showing that thymocytes lack suitable transporters for its uptake (Vara-Ciruelos et al., 2019) and that metformin failed to impact major AMPK-sensitive metabolic pathways in PBMCs and CD4 + T cells (Nicholas et al., 2019). As a result, we find it unlikely the increase in CD8 + EMRA T cells is influenced by the medications used. ...
... Since T2D is also characterised by metabolic imbalances we began to investigate T cell metabolism in the context of T2D. Mitochondria from T2D CD8 + T cells displayed a higher oxidative capacity, a phenomenon also observed in PBMCs isolated from people with T2D (Nicholas et al., 2017;Nicholas et al., 2019). This increased oxygen consumption from T2D CD8 + T cells did not equate to improved function, mitochondrial morphology showed T2D EMRA cells to be fragmented and the increased proton leak suggests more mitochondrial damage in T2D CD8 + T cells. ...
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Mitochondrial health and cellular metabolism can heavily influence the onset of senescence in T cells. CD8 ⁺ EMRA T cells exhibit mitochondrial dysfunction and alterations to oxidative phosphorylation, however, the metabolic properties of senescent CD8 ⁺ T cells from people living with type 2 diabetes (T2D) are not known. We show here that mitochondria from T2D CD8 ⁺ T cells had a higher oxidative capacity together with increased levels of mitochondrial reactive oxgen species (mtROS), compared to age-matched control cells. While fatty acid uptake was increased, fatty acid oxidation was impaired in T2D CD8 ⁺ EMRA T cells, which also showed an accumulation of lipid droplets and decreased AMPK activity. Increasing glucose and fatty acids in healthy CD8 ⁺ T cells resulted in increased p-p53 expression and a fragmented mitochondrial morphology, similar to that observed in T2D CD8 ⁺ EMRA T cells. The resulting mitochondrial changes are likely to have a profound effect on T cell function. Consequently, a better understanding of these metabolic abnormalities is crucial as metabolic manipulation of these cells may restore correct T cell function and help reduce the impact of T cell dysfunction in T2D.
... Beyond glycolytic activity, fatty acid metabolism also plays an important role in T cell mediated inflammation. In diabetic subjects, despite increased glycolytic activity in activated peripheral blood mononuclear cells (PBMCs), it was shown that Th17 inflammation was fueled by long chain fatty acids rather than by glucose itself [14]. ...
... The glycolytic rate was estimated indirectly through the surrogate marker of supernatant lactate concentration in PBMC in basal conditions and after stimulation with 2 µg/mL of both anti-CD3 and anti-CD28 antibodies (BD Biosciences, Heidelberg, Germany) for six hours. Several authors have shown that supernatant lactate concentration in this time frame reflects changes in glycolytic activity as estimated by extracellular acidification rate [14,[19][20][21]. After completion of activation treatment, tubes with activated and non-stimulated control cells were centrifuged at 400 × G for 5 min at 25 °C, and 200 µL of supernatant was stored at − 80 °C until use. ...
Article
Background Obesity promotes cellular immunometabolism changes that trigger the activation of macrophages and lymphocytes, leading to systemic inflammation. Activated leukocytes undergo metabolic reprogramming, increasing glycolytic activity.Objective To examine whether the reduction in the inflammatory state associated with bariatric surgery is associated with decreased glycolytic activity in leukocytes.SettingSingle-center, prospective observational study.Methods This study involved 18 patients with obesity undergoing bariatric surgery. All measurements were performed preoperatively and six months postoperatively. Peripheral blood mononuclear cells and plasma were obtained to determine the glycolytic rate and mitochondrial membrane potential as surrogates of the metabolic switching and high-sensitivity C-reactive protein, adipokines, and CD69 expression as inflammatory and activation markers.ResultsGlycolytic activity engaged by CD3/CD28 activation was reduced six months after bariatric surgery, associated with decreased levels of T helper (Th) 1 and Th17 signature cytokines. An overall reduction in inflammatory markers was observed, which correlated with a higher adiponectin/leptin ratio.Conclusions Metabolic and bariatric surgery-induced weight loss leads to reprogramming in T cells’ metabolic machinery, resulting in reduced stimulation of glycolysis after activation, which may explain the decrease in systemic inflammation mediated by cytokines such as interferon-γ and interleukin-17A.
... In our study participants, increased plasma concentrations of lactate and pyruvate, most likely of host origin, correlated with several plasma long-chain acylcarnitines. Moreover, plasma levels of acylcarnitines were indirectly associated with higher Serratia ratio and increased Th17 gene expression signatures, in line with prior observations that an environment rich in long-chain acylcarnitines induces immune cells with compromised mitochondrial fatty acid oxidation to produce Th17 cytokines that define inflammation (Nicholas et al., 2019). Ultimately, higher acylcarnitines correlated with higher CD4:CD8 T cell ratio at month 12, whereas lower lactate and pyruvate levels were associated with an increase in CD4 T cell reconstitution at month 24 on cART. ...
Article
The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.
... However, participants baseline IL-6 and MCP-1 concentrations were similar to what was reported by Banitalebi et al. [32] after low-volume sprint interval training (≈1.20 pg/mL and 200 pg/mL, respectively), suggesting an absence of low-grade inflammation at baseline, and therefore, a limited potential for improvement. This hypothesis is also supported by the fact that participants of the present study had a less deteriorated lipid profile compared to the study of Zadeh et al. [33], which is a known factor that contribute to the risk of chronic inflammation [37]. ...
Article
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Background: The objective was to compare the effects of low-volume highintensity interval training (HIIT) to moderate-intensity continuous training (MICT) on the inflammatory profile in older women with type 2 diabetes (T2D). Methods: Thirty older physically inactive women (68 ± 5 years) with T2D were randomized in two groups: HIIT (75 min/week with 10 min/session at high intensity) or MICT (150 min/week). Inflammatory profile (IL-6, IL10, IL-15, TNF-α, and MCP-1; Luminex), body composition (iDXA), and cardiometabolic profile (A1c, glucose, insulin, lipids) were measured in fasting state, before and after the 3-month intervention in 27 participants. Results: While fasting levels of cytokines remained unchanged in the MICT group (p ≥ 0.18), circulating MCP-1 levels increased (from 160.9 [IQR: 133.5–230.2] to 187.88 [155.3–237.3]) in the HIIT group (p = 0.023). Linear regression revealed that changes in MCP-1 concentrations were positively associated with changes in A1c (adjusted R2 = 0.203; p = 0.018). Conclusions: The results of this study suggest that 12 weeks of either lowvolume HIIT or MICT do not improve inflammatory markers in older unfit women with T2D. The correlation between changes in A1c and MCP-1 levels support the role of hyperglycemia in low-grade inflammation.
... Berod et al. showed that the inhibition of ACC reduces Th17 differentiation and induces Treg differentiation [91]. Glycolyis is a key step involved in the induction of Th17 cells, an increase in long chain acylcarnitine, and a reduction in β-oxidation occuring together with Th17 differentiation and activation [92]. ...
Article
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Macrophages and lymphocytes demonstrate metabolic plasticity, which is dependent 19 partly on their state of activation and partly on the availability of various energy yielding and bio-20 synthetic substrates (fatty acids, glucose and amino acids). These substrates are essential to fuel-21 based metabolic reprogramming that is supports optimal immune function, including the inflam-22 matory response. In this review, we will focus on metabolism in macrophages and lymphocytes and 23 discuss the role of fatty acids in governing the phenotype, activation and functional status of these 24 important cells. We summarize the current understanding of the pathways of fatty acid metabolism 25 and related mechanisms of action as well as explore possible new perspectives in this exciting area 26 of research. 27<br/
... The mechanism underlying glycolysis leading to Th17 cell polarization may be mediated by fatty acid synthesis (FAS). Indeed, Th17 cell function is dependent on fatty acid metabolism, thereby implicating the synthesis of several essential fatty acid derivatives in the regulation of Th17 cell function (18). ...
Article
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Chronic inflammation plays an important role in the development of metabolic diseases. These include obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated fatty liver disease. The proinflammatory environment maintained by the innate immunity, including macrophages and related cytokines, can be influenced by adaptive immunity. The function of T helper 17 (Th17) and regulatory T (Treg) cells in this process has attracted attention. The Th17/Treg balance is regulated by inflammatory cytokines and various metabolic factors, including those associated with cellular energy metabolism. The possible underlying mechanisms include metabolism-related signaling pathways and epigenetic regulation. Several studies conducted on human and animal models have shown marked differences in and the important roles of Th17/Treg in chronic inflammation associated with obesity and metabolic diseases. Moreover, Th17/Treg seems to be a bridge linking the gut microbiota to host metabolic disorders. In this review, we have provided an overview of the alterations in and the functions of the Th17/Treg balance in metabolic diseases and its role in regulating immune response-related glucose and lipid metabolism.
... These pro-inflammatory immune cells, along with hypertrophic adipocytes, are responsible for increased serum inflammatory cytokines such as IL-6, C-reactive protein, and type I and type III interferons (Jagannathan-Bogdan et al. 2011;McLaughlin et al. 2014). This immune phenotype can be further distinguished between nondiabetic and diabetic people with obesity through increased Th17 inflammation driven by impaired immune cell oxidation of fatty acid metabolites (Ip et al. 2016;Nicholas et al. 2019). ...
... The conclusions of this study suggested that the inflammatory state obesity-dependent can be counteract by regulating Treg/Th17 balance through the suppression of STAT3 and the induction of STAT5 [126]. Furthermore it is known that lipotoxicity alters the Treg/Th17 ratio not only in AT but also in the gut and liver [127,128]. Moreover in obese subjects, it is shown that an IL-17 decrease promotes adipogenesis [93]. Th17 cells connect innate and adaptive immunity and play multiple roles: protective at the level of mucous membranes and pro-inflammatory in several inflammatory diseases including obesity [129][130][131]. ...
Article
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In the last few decades, obesity has increased dramatically in pediatric patients. Obesity is a chronic disease correlated with systemic inflammation, characterized by the presence of CD4 and CD8 T cell infiltration and modified immune response, which contributes to the development of obesity related diseases and metabolic disorders, including impaired glucose metabolism. In particular, Treg and Th17 cells are dynamically balanced under healthy conditions, but imbalance occurs in inflammatory and pathological states, such as obesity. Some studies demonstrated that peripheral Treg and Th17 cells exhibit increased imbalance with worsening of glucose metabolic dysfunction, already in children with obesity. In this review, we considered the role of adipose tissue immunomodulation and the potential role played by Treg/T17 imbalance on the impaired glucose metabolism in pediatric obesity. In the patient care, immune monitoring could play an important role to define preventive strategies of pediatric metabolic disease treatments.
... Oxygen consumption rate (OCR) was measured using the XF Cell Mito Stress test (Santa Clara, CA, USA) as previous reported [15]. Briefly, Oligomycin (selleck.cn, ...
Article
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MicroRNAs (miRNA) have been shown to be associated with tumor diagnosis, prognosis, and therapeutic response. MiR-328-3p plays a significant role in breast cancer growth; however, its actual function and how it modulates specific biological functions is poorly understood. Here, miR-328-3p was significantly downregulated in breast cancer, especially in patients with metastasis. Mitochondrial carnitine palmitoyl transferase 1a (CPT1A) is a downstream target gene in the miR-328-3p-regulated pathway. Furthermore, the miR-328-3p/CPT1A/fatty acid β-oxidation/stemness axis was shown responsible for breast cancer metastasis. Collectively, this study revealed that miR-328-3p is a potential therapeutic target for the treatment of breast cancer patients with metastasis, and also a model for the miRNA-fatty acid β-oxidation-stemness axis, which may assist inunderstanding the cancer stem cell signaling functions of miRNA.
... Through this intervention, intracellular lipid accumulation decreased, AMPK signaling pathway, myocardial hypertrophy, and fibrosis were improved, with the reduced cardiomyocyte apoptosis. Oxidation of fatty acids generally produces acylcarnitine [22,23], and their accumulation may indicate low β-oxidation and changes in mitochondrial metabolism. However, energy metabolism inactivation flexibility in DCM patients is usually manifested as lipotoxicity. ...
Article
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Background Acylcarnitine is an intermediate product of fatty acid oxidation. It is reported to be closely associated with the occurrence of diabetic cardiomyopathy (DCM). However, the mechanism of acylcarnitine affecting myocardial disorders is yet to be explored. This current research explores the different chain lengths of acylcarnitines as biomarkers for the early diagnosis of DCM and the mechanism of acylcarnitines for the development of DCM in-vitro . Methods In a retrospective non-interventional study, 50 simple type 2 diabetes mellitus patients and 50 DCM patients were recruited. Plasma samples from both groups were analyzed by high throughput metabolomics and cluster heat map using mass spectrometry. Principal component analysis was used to compare the changes occurring in the studied 25 acylcarnitines. Multivariable binary logistic regression was used to analyze the odds ratio of each group for factors and the 95% confidence interval in DCM. Myristoylcarnitine (C14) exogenous intervention was given to H9c2 cells to verify the expression of lipid metabolism-related protein, inflammation-related protein expression, apoptosis-related protein expression, and cardiomyocyte hypertrophy and fibrosis-related protein expression. Results Factor 1 (C14, lauroylcarnitine, tetradecanoyldiacylcarnitine, 3-hydroxyl-tetradecanoylcarnitine, arachidic carnitine, octadecanoylcarnitine, 3-hydroxypalmitoleylcarnitine) and factor 4 (octanoylcarnitine, hexanoylcarnitine, decanoylcarnitine) were positively correlated with the risk of DCM. Exogenous C14 supplementation to cardiomyocytes led to increased lipid deposition in cardiomyocytes along with the obstacles in adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways and affecting fatty acid oxidation. This further caused myocardial lipotoxicity, ultimately leading to cardiomyocyte hypertrophy, fibrotic remodeling, and increased apoptosis. However, this effect was mitigated by the AMPK agonist acadesine. Conclusions The increased plasma levels in medium and long-chain acylcarnitine extracted from factors 1 and 4 are closely related to the risk of DCM, indicating that these factors can be an important tool for DCM risk assessment. C14 supplementation associated lipid accumulation by inhibiting the AMPK/ACC/CPT1 signaling pathway, aggravated myocardial lipotoxicity, increased apoptosis apart from cardiomyocyte hypertrophy and fibrosis were alleviated by the acadesine.
... Human studies interrogating T cell activation in people with obesity show mixed findings. Obesity has been associated with increased Th1 cells in human adipose and fatty acid metabolites, which activate Th17 T cell inflammation in blood (11,17). However, studies have also suggested that Th1 T cells from people with obesity are impaired and not hyperactivated. ...
Article
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Despite studies implicating adipose tissue T cells (ATT) in the initiation and persistence of adipose tissue inflammation, fundamental gaps in knowledge regarding ATT function impedes progress towards understanding how obesity influences adaptive immunity. We hypothesized ATT activation and function would have tissue-resident specific properties and that obesity would potentiate their inflammatory properties. We assessed ATT activation and inflammatory potential within mouse and human stromal vascular fraction (SVF). Surprisingly, murine and human ATTs from obese visceral white adipose tissue exhibited impaired inflammatory characteristics. Both environmental and cell-intrinsic factors are implicated in ATT dysfunction. Soluble factors from obese SVF inhibit ATTs activation. Additionally, chronic signaling through the T cell receptor is necessary for ATT impairment in obese adipose tissue but is independent of increased PD1 expression. To assess intracellular signaling mechanisms responsible for ATT inflammation impairments, single-cell RNA sequencing of ATTs was performed. ATTs in obese adipose tissue exhibit gene expression resembling T cell exhaustion and increased expression of co-inhibitory receptor Btla. In sum, this work suggests that obesity-induced ATT cells have functional characteristics and gene expression resembling T cell exhaustion, which is dependent upon localized soluble factors and cell-to-cell interactions in adipose tissue.
... Thus, the reliance on beta-oxidation by macrophages and T cells do not appear to drive their differentiation but likely support their maintenance or functionality. A defect in beta-oxidation also results in the accumulation of acyl-L-carnitine, which promotes IL-17 cytokine production and thus differentiation of T cells towards Th17 cells [31]. ...
Article
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Cell survival, proliferation and function are energy-demanding processes, fuelled by different metabolic pathways. Immune cells like any other cells will adapt their energy production to their function with specific metabolic pathways characteristic of resting, inflammatory or anti-inflammatory cells. This concept of immunometabolism is revolutionising the field of immunology, opening the gates for novel therapeutic approaches aimed at altering immune responses through immune metabolic manipulations. The first part of this review will give an extensive overview on the metabolic pathways used by immune cells. Diet is a major source of energy, providing substrates to fuel these different metabolic pathways. Protein, lipid and carbohydrate composition as well as food additives can thus shape the immune response particularly in the gut, the first immune point of contact with food antigens and gastrointestinal tract pathogens. How diet composition might affect gut immunometabolism and its impact on diseases will also be discussed. Finally, the food ingested by the host is also a source of energy for the micro-organisms inhabiting the gut lumen particularly in the colon. The by-products released through the processing of specific nutrients by gut bacteria also influence immune cell activity and differentiation. How bacterial metabolites influence gut immunometabolism will be covered in the third part of this review. This notion of immunometabolism and immune function is recent and a deeper understanding of how lifestyle might influence gut immunometabolism is key to prevent or treat diseases.
... Undoubtedly, there is a link between the disease and an impaired immune system, but the molecular mechanisms involved in altered immune cell function in diabetic patients are still unknown. Dysfunctional T cells may play a pivotal role in immunological impairment in diabetes mellitus (6). However, the precise effects of chronic hyperglycemia on immune cell function are still uncertain since contradictory findings of both hyperresponsive (7) and attenuated (8,9) T cells were reported in type 2 diabetic patients. ...
Article
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People with diabetes mellitus have an increased risk for infections, however, there is still a critical gap in precise knowledge about altered immune mechanisms in this disease. Since diabetic INS C94Y transgenic pigs exhibit elevated blood glucose and a stable diabetic phenotype soon after birth, they provide a favorable model to explore functional alterations of immune cells in an early stage of diabetes mellitus in vivo. Hence, we investigated peripheral blood mononuclear cells (PBMC) of these diabetic pigs compared to non-diabetic wild-type littermates. We found a 5-fold decreased proliferative response of T cells in INS C94Y tg pigs to polyclonal T cell mitogen phytohemagglutinin (PHA). Using label-free LC-MS/MS, a total of 3,487 proteins were quantified, and distinct changes in protein abundances in CD4 + T cells of early-stage diabetic pigs were detectable. Additionally, we found significant increases in mitochondrial oxygen consumption rate (OCR) and higher basal glycolytic activity in PBMC of diabetic INS C94Y tg pigs, indicating an altered metabolic immune cell phenotype. Thus, our study provides new insights into molecular mechanisms of dysregulated immune cells triggered by permanent hyperglycemia.
... In patients with type 2 diabetes, blocking CPT1A or inhibiting FAO led to less IL-17 production by proinflammatory Th17 cells. This indicates that FAO may activate Th17 inflammation in human type 2 diabetes [20]. Since inflammation contributes to insulin resistance and islet β cell dysfunction in type 2 diabetes, suppressing FAO in Th17 cell seems to be an effective way to relieve this disease. ...
Article
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CD4+ T cells play a vital role in the adaptive immune system and are involved in the pathogenesis of many diseases, including cancer, autoimmune diseases, and chronic inflammation. As an important mechanism for energy storage, a lot of researches have clarified that metabolism imbalance interacts with immune disorder, and one leads to the other. Lipid metabolism has close relationship with CD4+ T cells. In this review, we discuss fatty acid, cholesterol, prostaglandin, and phospholipid metabolism in CD4+ T cell subsets. Fatty acid β-oxidation (FAO) is activated in Th17 cell to support the proinflammatory function. Cholesterol promotes Th1, Th2, and Treg cell differentiation. In addition to glucose metabolism, lipid metabolism is also very important for immunity. Here, it is highlighted that lipid metabolism regulates CD4+ T cell differentiation and function and is related to diseases.
... Disruption in the balance between pro-inflammatory T helper 17 cells (Th17) and anti-inflammatory regulatory T cells (Treg) is a wellknown hallmark of chronic tissue inflammation [49][50][51] . Chronic metabolic disorders, such as diabetes, promote the expansion and polarization of Th17 cells [52][53][54] , and interference with this process has been shown to mitigate diabetic symptoms in patients 55 . Spleens of both control and Mof +/− animals displayed increased frequencies of Th17 cells and concomitant decreases in the Treg cell population under HFD conditions ( Supplementary Fig. 4k). ...
Article
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Noncommunicable diseases (NCDs) account for over 70% of deaths world-wide. Previous work has linked NCDs such as type 2 diabetes (T2D) to disruption of chromatin regulators. However, the exact molecular origins of these chronic conditions remain elusive. Here, we identify the H4 lysine 16 acetyltransferase MOF as a critical regulator of central carbon metabolism. High-throughput metabolomics unveil a systemic amino acid and carbohydrate imbalance in Mof deficient mice, manifesting in T2D predisposition. Oral glucose tolerance testing (OGTT) reveals defects in glucose assimilation and insulin secretion in these animals. Furthermore, Mof deficient mice are resistant to diet-induced fat gain due to defects in glucose uptake in adipose tissue. MOF-mediated H4K16ac deposition controls expression of the master regulator of glucose metabolism, Pparg and the entire downstream transcriptional network. Glucose uptake and lipid storage can be reconstituted in MOF-depleted adipocytes in vitro by ectopic Glut4 expression, PPARγ agonist thiazolidinedione (TZD) treatment or SIRT1 inhibition. Hence, chronic imbalance in H4K16ac promotes a destabilisation of metabolism triggering the development of a metabolic disorder, and its maintenance provides an unprecedented regulatory epigenetic mechanism controlling diet-induced obesity.
... Pro-inflammatory Th1 cells produce IFN-γ and play an essential role in the development of obesity [8]. Additionally, lipotoxicity, recorded in obesity, leads to an imbalance of Treg and Th17 cells in the intestine, AT, and liver and to changes in their functional properties [9][10][11]. However, IL-17 levels decline as obesity progresses and promotes adipogenesis [12]. ...
Article
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Obesity is a metabolic disease characterized by a chronic subclinical inflammatory response associated with an imbalance/dysregulation of cellular homeostasis in response to excessive nutrient intake and accumulation. CD4+ Tlymphocytes form different populations, Th1, Th2, Th9, Th17, Th22, and Treg cells, which have phenotypic and functional differences. Despite the active study of Th17 cells in severe disorders, their role in metabolic disorders, particularly in obesity, is not well understood. Th17 lymphocytes, depending on the microenvironment, can form pathogenic and nonpathogenic subpopulations. Systemic inflammation induces the reprogramming of the transcriptome of normal Th17 cells formed in epithelial tissues, which acquire new properties. A zone of overlapping states exists between IL-17A-producing cells, which does not allow a clear boundary between non-pathogenic Th17 and pathogenic Th17 lymphocytes. We assume that in obesity, the pool of inflammatory pathogenic Th17 cells with cytotoxic potential is a fraction of terminally differentiated memory lymphocytes and is responsible for developing autoimmune reactions.
... Furthermore, we show that Hh signaling influences the metabolic regulation of Th17 cells through a known non-canonical Hh signaling axis via CaMKK2/LKB1 and pAMPK in adipose tissue 24 . This is in line with published data indicating a role of pAMPK in human and murine Th17 polarization 29,30 and in the pathogenicity of Th17 cells in a model of adoptive T cell transfer colitis 29 . Our model is summarized in Suppl. ...
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Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell fate decisions during embryogenesis and adult tissue patterning. Here we find that cell-autonomous Hedgehog signaling, independent of exogenous ligands, selectively drives the polarization of Th17 cells but not other T helper cell subsets. We show that endogenous Hedgehog ligand, Ihh, signals to activate both canonical and non-canonical Hedgehog pathways through Gli3 and AMPK. We demonstrate that Hedgehog pathway inhibition with either the clinically-approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4+ T cells greatly diminishes disease severity in two mouse models of intestinal inflammation. We confirm that Hedgehog pathway expression is upregulated in tissue from human ulcerative colitis patients and correlates with Th17 marker expression. This work implicates Hedgehog signaling in Th17 polarization and intestinal immunopathology and indicates the potential therapeutic use of Hedgehog inhibitors in the treatment of inflammatory bowel disease. Th17 cells are critical players in the immunopathology of a range of autoimmune diseases. Here the authors implicate Hedgehog signaling in Th17 polarization and in the immunopathology of intestinal inflammation in murine models and suggest therapeutic targeting of Hedgehog signaling in the context of inflammatory bowel disease.
... Similar results were found by a study on the toxicity of PFOA with human liver cells (Peng et al., 2013). Adversely, the increased levels of acylcarnitines led to oxidative stress (Aguer et al., 2015) and inflammation due to the activation of cytokines and expression of COX-2 (Aguer et al., 2015;Nicholas et al., 2019). ...
Article
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PFHxS (Perfluorohexane sulfonic acid) is one of the short-chain perfluoroalkyl substances (PFASs) which are widely used in many industrial and consumer applications. However, limited information is available on the molecular mechanism of PFHxS toxicity (e.g. lipid metabolism). This study provides in-depth information on the lipid regulation of zebrafish embryos with and without PFHxS exposure. Lipid changes throughout zebrafish development (4to 120 h post fertilization (hpf)) were closely associated with lipid species and lipid composition (fatty acyl chains). A comprehensive lipid analysis of four different PFHxS exposures (0, 0.3, 1, 3, and 10 μM) at different zebrafish developmental stages (24, 48, 72, and 120 hpf) was performed. Data on exposure concentration, lipids, and developmental stage showed that all PFHxS concentrations dysregulated the lipid metabolism and these were developmental-dependent. The pattern of significantly changed lipids revealed that PFHxS caused effects related to oxidative stress, inflammation, and impaired fatty acid β-oxidation. Oxidative stress and inflammation caused the remodeling of glycerophospholipid (phosphatidylcholine (PC) and phosphatidylethanolamine (PE)), with increased incorporation of omega-3 PUFA and a decreased incorporation of omega-6 PUFA.
... The role of Th17 cells and Regulatory T cells (Treg) in this process has been less clear. In recent years, some researchers have described novel pathological mechanisms of Th17 cells, Treg cells and associated cytokines in T2DM [6][7][8]. ...
Article
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Purpose The aim of this study was to investigate the changes of Helper T cells 17 (Th17 cells), Regulatory T cells (Treg cells), Treg/Th17, Interleukin-17 (IL-17) and Interleukin-10 (IL-10) in patients with type 2 diabetes mellitus (T2DM). Methods Four electronic resource databases were searched from their inception to 1 August 2021. Case-control studies about changes of Th17 cells, Treg cells, Treg/Th17, IL-17 and IL-10 in patients with T2DM were retrieved. We performed this meta-analysis via RevMan V.5.3 and Stata14. Results 20 studies with 1242 individuals were included in the meta-analysis. Compared with the controls, the patients with T2DM had significantly increased levels of percentage of Th17 cells (SMD, 1.74; 95% CI, 0.47–3.01; p < 0.001), IL-17 (SMD, 2.17; 95% CI, 0.06–4.28; p < 0.001), IL-10 (SMD, 1.20; 95% CI, 0.81–1.59; p = 0.003), but decreased levels of percentage of Treg cells (SMD, −1.17; 95% CI, −2.22 to −0.13; p < 0.001) and Treg/Th17 ratio (SMD, −4.43; 95% CI, −7.07 to −1.78; p < 0.001). Subgroup analysis showed that percentage of CD4⁺CD25⁺FOXP3⁺ Tregs (SMD, −2.36; 95% CI, −3.19 to −1.52; p = 0.003) in patients was notably lower than controls. While not significant changes were found in the percentage of CD4⁺CD25⁺Tregs (SMD, 0.03; 95% CI, −0.34–0.40; p = 0.63) between patients and controls. For plasma or serum IL-10, a higher plasma IL-10 level (SMD,1.37; 95% CI, 0.92–1.82; p = 0.01) was observed in T2DM. While serum IL-10 (SMD, 0.73; 95% CI, 0.35–1.12; p = 0.79) had no obvious difference between patients and controls. For ELISA or flow cytometry, IL-10 (SMD, 1.2; 95% CI, 0.71–1.70; p = 0.001) was higher in T2DM patients by using detection method of ELISA. Yet IL-10 using flow cytometry and subgroup analysis of IL-17 had no significant differences. Conclusions Adaptive immune system indeed plays an essential role in the process of T2DM. Imbalance between Th17 and Treg triggers pro-inflammatory environment in patients with T2DM.
... Therefore, there was not a specific trend with regard to changes in blood ACs in pre-SCM cows. Acylcarnitines derive from defective fatty acid b-oxidation in mitochondria [26] and they have been shown to affect cytokine production in T helper-17 (Th17 cells) [27]. Additionally, high ACs are correlated with the increased presence of pro-inflammatory mediators such as toll-like receptor (TLR), TNF, and interleukin-8 (IL-8) [28]. ...
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Subclinical mastitis (SCM) is a very common disease of dairy cows. Currently, somatic cell count (SCC) is used for SCM diagnoses. There are no prognostic tests to detect which cows may develop SCM during the dry-off period. Therefore, the objectives of this study were to identify metabolic alterations in the serum of pre-SCM cows during the dry-off period, at −8 and −4 weeks before calving, through a targeted mass spectrometry (MS) assay. Fifteen cows, free of any disease, and 10 cows affected only by SCM postpartum served as controls (CON) and the SCM group, respectively. Results showed 59 and 47 metabolites that differentiated (p ≤ 0.05) CON and pre-SCM cows at –8 and −4 weeks prior to the expected date of parturition, respectively. Regression analysis indicated that a panel of four serum metabolites (AUC = 0.92, p < 0.001) at −8 weeks and another four metabolites (AUC = 0.92, p < 0.01) at −4 weeks prior to parturition might serve as predictive biomarkers for SCM. Early identification of susceptible cows can enable development of better preventive measurements ahead of disease occurrence.
... Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system [1][2][3][4][5][6][7] , although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. ...
Article
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Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1–7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.
... These pro-inflammatory immune cells, along with hypertrophic adipocytes, are responsible for increased serum inflammatory cytokines such as IL-6, C-reactive protein, and type I and type III interferons (Jagannathan-Bogdan et al. 2011;McLaughlin et al. 2014). This immune phenotype can be further distinguished between nondiabetic and diabetic people with obesity through increased Th17 inflammation driven by impaired immune cell oxidation of fatty acid metabolites (Ip et al. 2016;Nicholas et al. 2019). ...
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This book provides a comprehensive assessment of obesity in Saudi Arabia, considering both the health and economic burdens posed to the country. It represents and further builds on a strong commitment by the Saudi government to address the rising problem of obesity in the country—particularly among youth. While obesity is complex, evidence-based interventions do exist and can focus on an integrated, systems-based approach to maximize impact. Additionally, effective implementation and monitoring of interventions to increase healthy diet, boost physical activity, and encourage a healthier lifestyle overall are critical for reducing obesity’s health and economic burdens and thus the overall obesity and NCD burden in Saudi Arabia
... The mechanisms causing progression from a metabolically healthy obese state to metabolic disease are still under investigation. Remarkably, mitochondria from type 2 diabetes patients appear altered in their function to promote Th17 cytokine production (26). Although much progress has been made over the past decade (27,28), further studies stratifying metabolically healthy and diseased PWO are still required to elucidate the underlying processes. ...
Article
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Over the past decades, the relationship between the immune system and metabolism has become a major research focus. In this arena of immunometabolism the capacity of adipose tissue to secrete immunomodulatory molecules, including adipokines, within the underlying low-grade inflammation during obesity brought attention to the impact obesity has on the immune system. Adipokines, such as leptin and adiponectin, influence T cell differentiation into different T helper subsets and their activation during immune responses. Furthermore, within the cellular milieu of adipose tissue nutrient availability regulates differentiation and activation of T cells and changes in cellular metabolic pathways. Upon activation, T cells shift from oxidative phosphorylation to oxidative glycolysis, while the differential signaling of the kinase mammalian target of rapamycin (mTOR) and the nuclear receptor PPARγ, amongst others, drive the subsequent T cell differentiation. While the mechanisms leading to a shift from the typical type 2-dominated milieu in lean people to a Th1-biased pro-inflammatory environment during obesity are the subject of extensive research, insights on its impact on peripheral Th2-dominated immune responses become more evident. In this review, we will summarize recent findings of how Th2 cells are metabolically regulated during obesity and malnutrition, and how these states affect local and systemic Th2-biased immune responses.
... In diabetic patients, due to the relative or absolute lack of insulin, the body is more dependent on fat for energy, and mitochondrial fatty acid beta oxidation activity increases. In addition, several studies have shown that the b-oxidation activity of peroxisomal fatty acids is enhanced in diabetes (4)(5)(6)(7)(8). In summary, studies have shown that fatty acid b-oxidation activity is increased in patients with diabetes, which is consistent with the upregulation of fatty acid degradation pathway enrichment in the disease group after treatment/before treatment in this study. ...
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Objective To use systems biology to explore the biomolecular network mechanism of the Jiangtang Tiaozhi Recipe (JTTZR) in the intervention of obese Type 2 diabetes (T2DM) patients with dyslipidemia. Methods Twelve patients with obese type 2 diabetes mellitus and dyslipidemia (traditional Chinese medicine syndrome differentiation was excess heat syndrome of the stomach and intestines) were treated with JTTZR for 24 weeks, and 12 patients were included in the healthy control group. First, blood samples from 6 patients in each group (disease group before treatment, disease group after treatment, and healthy control group) were collected for RNA microarray analysis. Quantitative polymerase chain reaction (qPCR) was used to validate these target lncRNAs and mRNAs. Finally, a detailed analysis of the differences in the disease group before treatment vs. the healthy control group and the disease group after treatment vs. the disease group before treatment was undertaken. In addition, we focused on disease-related pathways and analyzed the correlation between the differential expression of target lncRNAs and clinical indicators. Results (1) Disease group before treatment vs. healthy control group: There were 557 up-regulated lncRNAs, 273 down-regulated lncRNAs, 491 up-regulated mRNAs, and 1639 down-regulated mRNAs. GO analysis and pathway analysis showed that T2DM may be related to cell proliferation in the forebrain, post-embryonic organ development, calcium signaling pathway. qPCR validation showed that the expression of XLOC-005590 and HNF1A-AS1 as target lncRNAs increased, and this was verified by gene chip analysis. (2) Disease group after treatment vs. disease group before treatment: 128 lncRNAs were upregulated, 32 lncRNAs were downregulated, 45 mRNAs were upregulated, and 140 mRNAs were downregulated. GO analysis and pathway analysis showed that JTTZR may treat T2DM through endosome transport, the insulin signaling pathway, and glycine, serine, and threonine metabolism. qPCR validation showed that in the healthy control group, XLOC_005590 was upregulated, whereas the downstream gene (ECI2) was downregulated in the disease group before treatment. However, after 24 weeks of intervention with JTTZR, XLOC_005590 was downregulated and ECI2 was upregulated compared with the disease group before treatment (0 weeks) ( P < 0.05). Conclusion JTTZR may interfere in patients with obese T2DM with dyslipidemia by regulating pathways such as fatty acid degradation, glycolysis/gluconeogenesis, and pyruvate metabolism.
... July 2022 | Volume 9 | Article 945917 inflammation (Herbert et al., 2018). Fatty acid synthesis appears to drive the formation of Th17 cells (Young et al., 2017;Nicholas et al., 2019). Polyunsaturated fatty acids can induce thrombosis and proinflammation, resulting in an increased prevalence of atherosclerosis, obesity, and diabetes (Simopoulos, 2013;Kromhout and de Goede, 2014;Simopoulos, 2016). ...
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Aim: Psoriasis vulgaris (PV) is a complicated autoimmune disease characterized by erythema of the skin and a lack of available cures. PV is associated with an increased risk of metabolic syndrome and cardiovascular disease, which are both mediated by the interaction between systemic inflammation and aberrant metabolism. However, whether there are differences in the lipid metabolism between different levels of severity of PV remains elusive. Hence, we explored the molecular evidence for the subtyping of PV according to alterations in lipid metabolism using serum metabolomics, with the idea that such subtyping may contribute to the development of personalized treatment. Methods: Patients with PV were recruited at a dermatology clinic and classified based on the presence of metabolic comorbidities and their Psoriasis Area and Severity Index (PASI) from January 2019 to November 2019. Age- and sex-matched healthy controls were recruited from the preventive health department of the same institution for comparison. We performed targeted metabolomic analyses of serum samples and determined the correlation between metabolite composition and PASI scores. Results: A total of 123 participants, 88 patients with PV and 35 healthy subjects, were enrolled in this study. The patients with PV were assigned to a “PVM group” (PV with metabolic comorbidities) or a “PV group” (PV without metabolic comorbidities) and further subdivided into a “mild PV” (MP, PASI <10) and a “severe PV” (SP, PASI ≥10) groups. Compared with the matched healthy controls, levels of 27 metabolites in the MP subgroup and 28 metabolites in the SP subgroup were found to be altered. Among these, SM (d16:0/17:1) and SM (d19:1/20:0) were positively correlated with the PASI in the MP subgroup, while Cer (d18:1/18:0), PC (18:0/22:4), and PC (20:0/22:4) were positively correlated with the PASI in the SP subgroup. In the PVM group, levels of 17 metabolites were increased, especially ceramides and phosphatidylcholine, compared with matched patients from the PV group. In addition, the correlation analysis indicated that Cer (d18:1/18:0) and SM (d16:1/16:1) were not only correlated with PASI but also has strongly positive correlations with biochemical indicators. Conclusion: The results of this study indicate that patients with PV at different severity levels have distinct metabolic profiles, and that metabolic disorders complicate the disease development. These findings will help us understand the pathological progression and establish strategies for the precision treatment of PV.
Article
A disparate array of plasma/serum markers provide evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and meta-flammation. These remain largely non-actionable, and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Tregs) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting Th17 or Th1 cytokine production, respectively. These data suggest that Treg control of Teff metabolism controls inflammation differentially in prediabetes compared to type 2 diabetes. Queries of genes that impact mitochondrial function and/or pathways leading to transcription of lipid metabolism genes identified the fatty acid importer CD36 as highly expressed in Tregs but not Teff from prediabetes subjects. Pharmacological blockade of CD36 in Tregs from prediabetes subjects decreased Teff production of the Th17 cytokines that differentiate overall prediabetes inflammation. We conclude Tregs control CD4+ T cell cytokine profiles through mechanisms determined, at least in part, by host metabolic status. Furthermore, Treg CD36 uniquely promotes Th17 cytokine production by Teff in prediabetes.
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Recently, some metabolites in skin interstitial fluid (SIF) have become emerging re×sources for early disease diagnosis. However, their low level in SIF and difficulty to sampling are the biggest obstacle to further potential application. Here, a swellable microneedle array patch (MNAP) with high mechanical strength is presented, and the rapid enrichment of positively charged metabolites is achieved. The MNAP is fabricated by poly (chondroitin sulfate‐acrylamido‐2‐methylpropane sulfonic acid)‐gold nanoparticles (GNPs) composites via a micro‐molding. The negatively charged copolymer hydrogel not only enrich positively charged metabolites, but also provide swellable capacity. The in situ synthesis of GNPs in the process of copolymerization make the GNPs cross‐link to the hydrogel, which further enhance the MNAP mechanical strength and enrichment efficiency for positively charged metabolites. By using the MNAP, around 5 mg SIF in 10 min from the high fat/cholecalciferol/methimazole‐induced atherogenesis rat is extracted and 23 metabolites including 13 quaternary ammonium cationic compounds can be detected and quantified by using a LC‐QTOF‐MS. Dysregulated L‐carnitine and choline metabolism are discovered a week earlier in the SIF than in the serum, achieving early diagnosis of the metabolism syndrome disease. This MNAP also helps users complete home sampling for early disease diagnosis and monitoring. A swellable microneedle array patch (MNAP) with high mechanical strength and rapid enrichment of cationic metabolites is presented, which is fabricated by poly (chondroitin sulfate‐acrylamido‐2‐methylpropane sulfonic acid)‐gold nanoparticles composites. By using the MNAP, ≈ 5 mg skin interstitial fluid from high fat/cholecalciferol/methimazole‐induced atherogenesis rats is extracted and 23 metabolites can be detected by using LC‐QTOF‐MS.
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T helper 17 (Th17) cells play a key role in barrier protection against fungal and bacterial pathogens but are also pathological drivers of many inflammatory diseases. Although the transcription factor networks governing Th17 differentiation are well defined, the signaling pathways that regulate the development and function of this important CD4 ⁺ T cell subset are still poorly understood. Hedgehog (Hh) signaling plays important roles in regulating cell fate decisions during embryogenesis and adult tissue patterning. Using novel CD4-specific Hh knockout mice, we find that intracellular Hh signaling, independently of exogenous Hh ligands, selectively drives Th17 lineage differentiation but not the development of Th1, Th2, or iTreg CD4 ⁺ Th cells. We show that the endogenous Indian Hh (Ihh) ligand signals via the signal transducer Smoothened to activate both canonical and non-canonical Hh pathways, through the Gli3 transcription factor and AMPK phosphorylation, respectively. Using two models of intestinal inflammation, we demonstrate that inhibition of the Hh pathway with either the clinically approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4 ⁺ T cells greatly diminishes disease severity. Taken together, we have uncovered Hh as a novel signaling pathway controlling Th17 differentiation and Gli3 as a crucial transcription factor in this process. Our work paves the way for a potential use of Hh inhibitors in the treatment of inflammatory bowel disease and other autoimmune diseases.
Article
T helper type 17 (Th17) cells are characterized by inherent plasticity and heterogeneity displaying both pathogenic and tissue‐protective functions. Emerging evidence has illuminated a pivotal role for metabolic reprogramming in shaping Th17 cell fate determination. Metabolic responses are regulated by a constellation of factors and environmental triggers, including cytokines, nutrients, oxygen levels and metabolites. Dysregulation of metabolic pathways not only influences Th17 cell plasticity and effector function but affects the outcome of Th17‐linked autoimmune, inflammatory and anti‐tumor responses. Understanding the molecular mechanisms underpinning metabolic reprogramming can allow the enhancement of protective Th17 cell‐mediated responses during infections and cancer, concomitant with suppression of detrimental Th17 processes during autoimmune and inflammatory diseases. In the present review, we describe major metabolic pathways underlying the differentiation of Th17 cells and their crosstalk with intracellular signaling mediators, we discuss how metabolic reprogramming affects Th17 cell plasticity and functions and, finally, we outline current advances in the exploitation of metabolic checkpoints for the development of novel therapeutic interventions for the management of tissue inflammation, autoimmune disorders and cancer.
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The appreciation of metabolic regulation of T cell function has exploded over the past decade, as has our understanding of how inflammation fuels comorbidities of obesity, including type 2 diabetes. The likelihood that obesity fundamentally alters T cell metabolism and thus chronic obesity-associated inflammation is high, but studies testing causal relationships remain under-represented. We searched PubMed for key words including mitochondria, obesity, T cell, type 2 diabetes, cristae, fission, fusion, redox, and reactive oxygen species to identify foundational and more recent studies that address these topics or cite foundational work. We investigated primary papers cited by reviews found in these searches, and highlight recent work with >100 citations to illustrate the state of the art in understanding mechanisms that control metabolism and thus function of various T cell subsets in obesity. However, “popularity” of a paper over the first 5 years after publication cannot assess long-term impact; thus some likely important work with fewer citations is also highlighted. We feature studies of human cells, supplementing with studies from animal models that suggest future directions for human cell research. This approach identified gaps in the literature that will need filled before we can estimate efficacy of mitochondria-targeted drugs in clinical trials to alleviate pathogenesis of obesity-associated inflammation.
Article
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 response is through changes in cellular metabolism. Methods We studied inflammation and cellular metabolism of 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 subjects with obesity had lower oxidative metabolism and 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 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.
Article
Objective: Myeloid cells dominate metabolic disease-associated inflammation (metaflammation) in mouse obesity, but the contributions of myeloid cells to the peripheral inflammation that fuels sequelae of human obesity are untested. This study used unbiased approaches to rank contributions of myeloid and T cells to peripheral inflammation in people with obesity across the spectrum of metabolic health. Methods: Peripheral blood mononuclear cells (PBMCs) from people with obesity with or without prediabetes or type 2 diabetes were stimulated with T cell-targeting CD3/CD28 or myeloid-targeting lipopolysaccharide for 20 to 72 hours to assess cytokine production using Bio-Plex. Bioinformatic modeling ranked cytokines with respect to their predictive power for metabolic health. Intracellular tumor necrosis factor α was quantitated as a classical indicator of metaflammation. Results: Cytokines increased over 72 hours following T cell-, but not myeloid-, targeted stimulation to indicate that acute myeloid inflammation may shift to T cell inflammation over time. T cells contributed more tumor necrosis factor α to peripheral inflammation regardless of metabolic status. Bioinformatic combination of cytokines from all cohorts, stimuli, and time points indicated that T cell-targeted stimulation was most important for differentiating inflammation in diabetes, consistent with previous identification of a mixed T helper type 1/T helper type 17 cytokine profile in diabetes. Conclusions: T cells dominate peripheral inflammation in obesity; therefore, targeting T cells may be an effective approach for prevention/management of metaflammation.
Article
Objective Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC. Design We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling. Results Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host–microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host–microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes. Conclusions Our data reveal that IgG4-SC and PSC possess divergent host–microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.
Article
Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal β -oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. SIGNIFICANCE STATEMENT: This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.
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Non-alcoholic fatty liver disease (NAFLD), which is considered a liver phenotype of metabolic diseases, is becoming a major cause of chronic liver disease. Multiple factors influence and interact with each other in a complex manner to form this pathological condition. As evidenced by low-grade chronic inflammation in obesity, which is a basic pathological feature of NAFLD, immune cell infiltration can occur in various organs, and immune cell infiltration into the liver plays an important role in the development of steatohepatitis. In recent years, an increasing number of reports indicate the involvement of innate immunity and adaptive immunity in the pathogenesis of NAFLD. CD4⁺ T-cells, which serve as an essential and complex element of the immune system and major regulators of host health and disease, are differentiated into functional T helper 1 (Th1), Th2, Th9, Th17, Th22, T follicular helper, and regulatory T-cells upon antigen stimulation in a special cytokine environment. In NAFLD patients, various pathological conditions such as obesity, diabetes, dyslipidemia, and adipose tissue inflammation coexist. Hence, T-cells can be affected by each of these pathological conditions. This review covers and discusses the reports on NAFLD and its associated pathologies as well as their effects on CD4⁺ T-cells.
Article
Objective To identify the role of fatty acid-binding protein-3 (FABP3) in vascular fibrosis in Takayasu’s arteritis (TAK) and to explore the underlying molecular mechanism. Methods The expression of FABP3 and extracellular matrix proteins (ECMs) were detected in aorta tissues from TAK patients (n = 12) and healthy controls (n = 8) by immunohistochemistry. The concentration of serum proteins was determined by ELISA. CCK8 and Ki67 staining were used to measure aorta adventitial fibroblasts (AAFs) proliferation. Widely-targeted lipidomic profiling was used to screen for associated metabolic pathways. Changes in ECMs and fatty acid oxidation (FAO) related enzymes were determined by RT-qPCR and Western blot. The interactions between FABP3 and these enzymes were explored with Co-immunoprecipitation (Co-IP) assay. Results The expression of FABP3 was increased in the thickened adventitia of TAK patients, and was positively correlated with the serum expression of ECMs. FABP3 knockdown inhibited AAF proliferation and ECMs production, whereas FABP3 overexpression enhanced these processes. Further analysis revealed that FABP3 upregulation promoted carnitine palmitoyltransferase 1A (CPT1A) and carnitine/acylcarnitine carrier protein (CACT) expressions, two key enzymes in FAO, as well as ATP levels. FABP3 and CACT were co-localized in the adventitia and bound to each other in AAFs. Etomoxir reversed the enhanced FAO, ATP production, AAF proliferation, and ECM production mediated by FABP3 upregulation. Treatment with 60 g/day curcumin granules for three months reduced the level of serum FABP3. Curcumin also inhibited vascular fibrosis by reducing FABP3-enhanced FAO in AAFs. Conclusion Elevated FABP3 expression accelerated vascular fibrosis in TAK, which was likely mediated by promoting FAO in AAFs.
Article
Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid. Neuroimaging data indicate that these inflammation-induced neurotransmitter effects manifest as decreased activation of ventral striatum and decreased functional connectivity in reward circuitry involving ventral striatum and ventromedial prefrontal cortex. Neurocircuitry changes in turn mediate nuanced effects on motivation that include decreased willingness to expend effort for reward while maintaining the ability to experience reward. Taken together, the data reveal an inflammation-induced pathophysiologic phenotype that is agnostic to diagnosis. Given the many mechanisms involved, this phenotype represents an opportunity for development of novel and/or repurposed pharmacological strategies that target inflammation and associated cellular and systemic immunometabolic changes and their downstream effects on the brain. To date, clinical trials have failed to capitalize on the unique nature of this transdiagnostic phenotype, leaving the field bereft of interpretable data for meaningful clinical application. However, novel trial designs incorporating established targets in the brain and/or periphery using relevant outcome variables (e.g., anhedonia) are the future of targeted therapy in psychiatry. SIGNIFICANCE STATEMENT: Emerging understanding of mechanisms by which peripheral inflammation can affect the brain and behavior has created unprecedented opportunities for development of pharmacological strategies to treat deficits in motivation including anhedonia, a core and disabling symptom of depression well represented in multiple psychiatric disorders. Mechanisms include inflammation and cellular and systemic immunometabolism and alterations in dopamine, glutamate, and kynurenine metabolites, revealing a target-rich environment that nevertheless has yet to be fully exploited by current clinical trial designs and drugs employed.
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Metabolic abnormalities substantially increase the risk of noncommunicable diseases, which are among the leading causes of mortality globally. Mitigating and preventing these adverse consequences remains challenging due to a limited understanding of metabolic health. Metabolic flexibility, a key tenet of metabolic health, encompasses the responsiveness of interrelated pathways to maintain energy homeostasis throughout daily physiologic challenges, such as the response to meal challenges. One critical underlying research gap concerns the measurement of postprandial metabolic flexibility, which remains incompletely understood. We concisely review the methodology for assessment of postprandial metabolic flexibility in recent human studies. We identify three commonalities of study design, specifically the nature of the challenge, nature of the response measured, and approach to data analysis. Primary interventions were acute short-term nutrition challenges, including single- and multiple-macronutrient tolerance tests. Post-meal challenge responses were measured via laboratory assays and instrumentation, based on a diverse set of metabolic flexibility indicators (e.g., energy expenditure [whole body indirect calorimetry], glucose and insulin kinetics, metabolomics, transcriptomics). Common standard approaches have been diabetes-centric with single-macronutrient challenges (oral glucose tolerance test) to characterize the postprandial response based on glucose and insulin metabolism; or broad measurements of energy expenditure with calculated macronutrient oxidation via indirect calorimetry. Recent methodological advances have included the use of multiple-macronutrient meal challenges that are more representative of physiologic meals consumed by free-living humans, combinatorial approaches for assays and instruments, evaluation of other metabolic flexibility indicators via precision health, systems biology, and temporal perspectives. Omics studies have identified potential novel indicators of metabolic flexibility, which provide greater granularity to prior evidence from canonical approaches. In summary, recent findings indicate the potential for an expanded understanding of postprandial metabolic flexibility, based on non-classical measurements and methodology, which could represent novel dynamic indicators of metabolic diseases.
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Background The efficacy of small molecule inhibitors for intracellular signal mediators varies among the individuals, and their mechanism of action is broad. A phosphodiesterase 4 inhibitor apremilast shows a dramatic effect on a certain proportion of psoriatic patients by modulating the cellular metabolism and regulating the production of pro-inflammatory molecules. However, it is unclear to which disease subtype this drug benefits. While psoriasis is a Th17-mediated disease, how immune cells are affected by the modulation of cellular metabolism is not fully evaluated, either. Objective This study aims to identify the indices which predict the efficacy of apremilast in psoriasis, and to investigate the impact of metabolic activity in immune cells on the psoriatic pathogenesis. Methods The association of treatment efficacy with clinical and laboratory data of the 58 psoriatic patients was evaluated. The reflector of the associated index was also sought among the indices of cellular metabolic pathways by use of an extracellular flux analyzer. Results There was a correlation between clinical improvement and the serum lactate dehydrogenase (LDH) level in the patients treated with apremilast but not in those with biologics. Serum LDH level did not correlate with the cutaneous disease severity but correlated with the oxygen consumption rate of blood T cells. Conclusion Psoriatic patients with high serum LDH level can be benefitted by apremilast. The serum LDH level reflects the augmented respiratory activity of T cells in psoriasis. Our results would highlight the importance of regarding metabolic skew in immune cells as a treatment target in psoriasis.
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The human microbiota is a unique set of microorganisms colonizing the human body and evolving within it from the very beginning. Acting as an insider, the microbiota provides nutrients, and mutualistically interacts with the host’s immune system, thus contributing to the generation of barriers against pathogens. While a strong link has been documented between intestinal dysbiosis (i.e., disruption to the microbiota homeostasis) and diseases, the mechanisms by which commensal bacteria impact a wide spectrum of mucosal and extramucosal human disorders have only partially been deciphered. This is particularly puzzling for multiple myeloma (MM), a treatable but incurable neoplasia of plasma cells that accumulate in the bone marrow and lead to end-organ damage. Here we revise the most recent literature on data from both the bench and the bedside that show how the gut microbiota modulates cancer immunity, potentially impacting the progression of asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) to full blown MM. We also explore the effect of the gut microbiome on hematopoietic stem cell transplantation, chemotherapy, immunomodulating therapy and cancer immunotherapy in MM patients. Additionally, we identify the most cogent area of investigation that have the highest chance to delineate microbiota-related and pathobiology-based parameters for patient risk stratification. Lastly, we highlight microbiota-modulating strategies (i.e., diet, prebiotics, probiotics, fecal microbiota transplantation and postbiotics) that may reduce treatment-related toxicity in patients affected by MM as well as the rates of undertreatment of SMM patients.
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Diabetes is a significant risk factor for meibomian gland dysfunction (MGD), but its mechanism is poorly understood. The main function of the meibomian glands (MGs) is to synthesize, store, and secrete lipids. In this study, we found that the amount of lipids in the meibomian acini in STZ-induced type 1 diabetic mice decreased, and the lipid droplets became larger and irregular. In all, 31 lipid subclasses were identified in the mouse MGs, which contained 1378 lipid species in total through lipidomics analysis based on LC-MS/MS. Diabetes caused a significant increase in the content of ceramides (Cer) in the MGs but a significant decrease in the ration of sphingomyelin to ceramides (SM/Cer). The quantity of meibocytes in diabetic mice was dramatically decreased, and the proliferation activity was alleviated, which may be associated with cell cycle arrest caused by diabetes-induced abnormal Cer metabolism in MGs. We found an increase in macrophage and neutrophils infiltration in the diabetic MGs, which may be related to the significant reduction of AcCa in diabetic MGs. Taken together, the results of the present study demonstrated that diabetes induced disruption of lipid homeostasis in MGs, which may mediate the decreased cell proliferation and increased inflammation caused by diabetes in MGs.
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Redox homeostasis is elemental for the normal physiology of all cell types. Cells use multiple mechanisms to regulate the redox balance tightly. The onset and progression of many metabolic and aging-associated diseases occur due to the dysregulation of redox homeostasis. Thus, it is critical to identify and therapeutically target mechanisms that precipitate abnormalities in redox balance. Reactive oxygen species (ROS) produced within the immune cells regulate homeostasis, hyperimmune and hypoimmune cell responsiveness, apoptosis, immune response to pathogens, and tumor immunity. Immune cells have both cytosolic and organelle-specific redox regulatory systems to maintain appropriate levels of ROS. Nicotinamide nucleotide transhydrogenase (NNT) is an essential mitochondrial redox regulatory protein. Dysregulation of NNT function prevents immune cells from mounting an adequate immune response to pathogens, promotes a chronic inflammatory state associated with aging and metabolic diseases, and initiates conditions related to a dysregulated immune system such as autoimmunity. While many studies have reported on NNT in different cell types, including cancer cells, relatively few studies have explored NNT in immune cells. This review provides an overview of NNT and focuses on the current knowledge of NNT in the immune cells.
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The pathophysiology underlying metabolic disease and Type 2 Diabetes (T2D) is a complex orchestration of deregulated metabolic pathways in multiple target tissues. Molecular interactions between white adipose tissue, the gastrointestinal tract, the gut microbiome, and the immune cells within each tissue depot contribute to the development of metabolic disease in diet-induced and genetic mouse models of obesity and in obese and insulin resistant humans. Next generation sequencing and comprehensive analyses of different tissue metabolomes in response to dietary and pharmacological interventions reveals novel molecular signatures, pathways and functional metabolites with therapeutic potential to enhance host health. These major advances in resolving cellular phenotype and function underscores the complexity of inter-organ interactions in metabolic disease. In this review, we discuss key immunomodulatory cell types and effector molecules from white adipose tissue, the gastrointestinal tract, and the gut microbiome and highlight their mechanisms of action that contribute to the pathophysiology of obesity and Metabolic Syndrome. Understanding the molecular cross-talk between metabolic tissues in response to chronic overnutrition may lead to the identification of novel therapeutic targets that can improve host metabolism throughout the lifespan.
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Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health. In obesity, chronic low-grade inflammation can occur in adipose tissue that can progress to systemic inflammation; this inflammation contributes to the development of insulin resistance, T2DM and other comorbidities. An improved understanding of adaptive immune cell dysregulation that occurs during obesity and its associated metabolic comorbidities, with an appreciation of sex differences, will be critical for repurposing or developing immunomodulatory therapies to treat obesity and/or T2DM-associated inflammation. This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward.
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Hypertensive disorders of pregnancy and maternal diabetes profoundly affect fetal and newborn growth, yet disturbances in intermediate metabolism and relevant mediators of fetal growth alterations remain poorly defined. We sought to determine whether there are distinct newborn screen metabolic patterns among newborns affected by maternal hypertensive disorders or diabetes in utero. A retrospective observational study investigating distinct newborn screen metabolites in conjunction with data linked to birth and hospitalization records in the state of California between 2005 and 2010. A total of 41,333 maternal–infant dyads were included. Infants of diabetic mothers demonstrated associations with short-chain acylcarnitines and free carnitine. Infants born to mothers with preeclampsia with severe features and chronic hypertension with superimposed preeclampsia had alterations in acetylcarnitine, free carnitine, and ornithine levels. These results were further accentuated by size for gestational age designations. Infants of diabetic mothers demonstrate metabolic signs of incomplete beta oxidation and altered lipid metabolism. Infants of mothers with hypertensive disorders of pregnancy carry analyte signals that may reflect oxidative stress via altered nitric oxide signaling. The newborn screen analyte composition is influenced by the presence of these maternal conditions and is further associated with the newborn size designation at birth. Substantial differences in newborn screen analyte profiles were present based on the presence or absence of maternal diabetes or hypertensive disorder of pregnancy and this finding was further influenced by the newborn size designation at birth. The metabolic health of the newborn can be examined using the newborn screen and is heavily impacted by the condition of the mother during pregnancy. Utilizing the newborn screen to identify newborns affected by common conditions of pregnancy may help relate an infant’s underlying biological disposition with their clinical phenotype allowing for greater risk stratification and intervention.
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Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.
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It has been suggested that some cancer cells rely upon fatty acid oxidation (FAO) for energy. Here we show that when FAO was reduced approximately 90% by pharmacological inhibition of carnitine palmitoyltransferase I (CPT1) with low concentrations of etomoxir, the proliferation rate of various cancer cells was unaffected. Efforts to pharmacologically inhibit FAO more than 90% revealed that high concentrations of etomoxir (200 μM) have an off-target effect of inhibiting complex I of the electron transport chain. Surprisingly, however, when FAO was reduced further by genetic knockdown of CPT1, the proliferation rate of these same cells decreased nearly 2-fold and could not be restored by acetate or octanoic acid supplementation. Moreover, CPT1 knockdowns had altered mitochondrial morphology and impaired mitochondrial coupling, whereas cells in which CPT1 had been approximately 90% inhibited by etomoxir did not. Lipidomic profiling of mitochondria isolated from CPT1 knockdowns showed depleted concentrations of complex structural and signaling lipids. Additionally, expression of a catalytically dead CPT1 in CPT1 knockdowns did not restore mitochondrial coupling. Taken together, these results suggest that transport of at least some long-chain fatty acids into the mitochondria by CPT1 may be required for anabolic processes that support healthy mitochondrial function and cancer cell proliferation independent of FAO.
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Nasopharyngeal carcinoma (NPC) has a particularly high prevalence in southern China, southeastern Asia and northern Africa. Radiation resistance remains a serious obstacle to successful treatment in NPC. This study aimed to explore the metabolic feature of radiation-resistant NPC cells and identify new molecular-targeted agents to improve the therapeutic effects of radiotherapy in NPC. Methods: Radiation-responsive and radiation-resistant NPC cells were used as the model system in vitro and in vivo. Metabolomics approach was used to illustrate the global metabolic changes. 13C isotopomer tracing experiment and Seahorse XF analysis were undertaken to determine the activity of fatty acid oxidation (FAO). qRT-PCR was performed to evaluate the expression of essential FAO genes including CPT1A. NPC tumor tissue microarray was used to investigate the prognostic role of CPT1A. Either RNA interference or pharmacological blockade by Etomoxir were used to inhibit CPT1A. Radiation resistance was evaluated by colony formation assay. Mitochondrial membrane potential, apoptosis and neutral lipid content were measured by flow cytometry analysis using JC-1, Annexin V and LipidTOX Red probe respectively. Molecular markers of mitochondrial apoptosis were detected by western blot. Xenografts were treated with Etomoxir, radiation, or a combination of Etomoxir and radiation. Mitochondrial apoptosis and lipid droplets content of tumor tissues were detected by cleaved caspase 9 and Oil Red O staining respectively. Liquid chromatography coupled with tandem mass spectrometry approach was used to identify CPT1A-binding proteins. The interaction of CPT1A and Rab14 were detected by immunoprecipitation, immunofluorescence and in situ proximity ligation analysis. Fragment docking and direct coupling combined computational protein-protein interaction prediction method were used to predict the binding interface. Fatty acid trafficking was measured by pulse-chase assay using BODIPY C16 and MitoTracker Red probe. Results: FAO was active in radiation-resistant NPC cells, and the rate-limiting enzyme of FAO, carnitine palmitoyl transferase 1 A (CPT1A), was consistently up-regulated in these cells. The protein level of CPT1A was significantly associated with poor overall survival of NPC patients following radiotherapy. Inhibition of CPT1A re-sensitized NPC cells to radiation therapy by activating mitochondrial apoptosis both in vitro and in vivo. In addition, we identified Rab14 as a novel CPT1A binding protein. The CPT1A-Rab14 interaction facilitated fatty acid trafficking from lipid droplets to mitochondria, which decreased radiation-induced lipid accumulation and maximized ATP production. Knockdown of Rab14 attenuated CPT1A-mediated fatty acid trafficking and radiation resistance. Conclusion: An active FAO is a vital signature of NPC radiation resistance. Targeting CPT1A could be a beneficial regimen to improve the therapeutic effects of radiotherapy in NPC patients. Importantly, the CPT1A-Rab14 interaction plays roles in CPT1A-mediated radiation resistance by facilitating fatty acid trafficking. This interaction could be an attractive interface for the discovery of novel CPT1A inhibitors.
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Lysine succinylation was recently identified as a post-translational modification in cells. However, the molecular mechanism underlying lysine succinylation remains unclear. Here, we show that carnitine palmitoyltransferase 1A (CPT1A) has lysine succinyltransferase (LSTase) activity in vivo and in vitro. Using a stable isotope labeling by amino acid in cell culture (SILAC)-based proteomics approach, we found that 101 proteins were more succinylated in cells expressing wild-type (WT) CPT1A compared with vector control cells. One of the most heavily succinylated proteins in this analysis was enolase 1. We found that CPT1A WT succinylated enolase 1 and reduced enolase enzymatic activity in cells and in vitro. Importantly, mutation of CPT1A Gly710 (G710E) selectively inactivated carnitine palmitoyltransferase (CPTase) activity but not the LSTase activity that decreased enolase activity in cells and promoted cell proliferation under glutamine depletion. These findings suggest that CPT1A acts as an LSTase that can regulate enzymatic activity of a substrate protein and metabolism independent of its classical CPTase activity.
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Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca²⁺ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα). These data indicate that metabolic and signal transduction defects present in T1D can be elicited ex vivo in isolated cells. Changes that precede T1D, including inflammation, may activate atypical responses in people that are genetically predisposed to T1D. To identify such cellular differences in T1D, we quantified a panel of metabolic responses in fibroblasts and peripheral blood cells (PBMCs) from age-matched T1D and non-T1D subjects, as models for non-immune and immune cells, respectively. Fibroblasts from T1D subjects accumulated more lipid, had higher LC-CoA levels and converted more FA to CO2, with less mitochondrial proton leak in response to oleate alone or with TNFα, using the latter as a model of inflammation. T1D-PBMCs contained and also accumulated more lipid following FA exposure. In addition, they formed more peroxidized lipid than controls following FA exposure. We conclude that both immune and non-immune cells in T1D subjects differ from controls in terms of responses to FA and TNFα. Our results suggest a differential sensitivity to inflammatory insults and FA that may precede and contribute to T1D by priming both immune cells and their targets for autoimmune reactions.
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Linking immunometabolic adaptation to T-cell function provides insight for the development of new therapeutic approaches in multiple disease settings. T-cell activation and downstream effector functions of CD4+ and CD8+ T-cells are controlled by the strength of interaction between the T-cell receptor (TCR) and peptides presented by human leukocyte antigens (pHLA). The role of TCR–pHLA interactions in modulating T-cell metabolism is unknown. Here, for the first time, we explore the relative contributions of the main metabolic pathways to functional responses in human CD4+ and CD8+ T-cells. Increased expression of hexokinase II accompanied by higher basal glycolysis is demonstrated in CD4+ T-cells; cytokine production in CD8+ T-cells is more reliant on oxidative phosphorylation. Using antigen-specific CD4+ and CD8+ T-cell clones and altered peptide ligands, we demonstrate that binding affinity tunes the underlying metabolic shift. Overall, this study provides important new insight into how metabolic pathways are controlled during antigen-specific activation of human T-cells.
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Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD⁺ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD⁺ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled.
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Metabolism has been shown to integrate with epigenetics and transcription to modulate cell fate and function. Beyond meeting the bioenergetic and biosynthetic demands of T-cell differentiation, whether metabolism might control T-cell fate by an epigenetic mechanism is unclear. Here, through the discovery and mechanistic characterization of a small molecule, (aminooxy)acetic acid, that reprograms the differentiation of T helper 17 (TH17) cells towards induced regulatory T (iTreg) cells, we show that increased transamination, mainly catalysed by GOT1, leads to increased levels of 2-hydroxyglutarate in differentiating TH17 cells. The accumulation of 2-hydroxyglutarate resulted in hypermethylation of the Foxp3 gene locus and inhibited Foxp3 transcription, which is essential for fate determination towards TH17 cells. Inhibition of the conversion of glutamate to α-ketoglutaric acid prevented the production of 2-hydroxyglutarate, reduced methylation of the Foxp3 gene locus, and increased Foxp3 expression. This consequently blocked the differentiation of TH17 cells by antagonizing the function of transcription factor RORγt and promoted polarization into iTreg cells. Selective inhibition of GOT1 with (aminooxy)acetic acid ameliorated experimental autoimmune encephalomyelitis in a therapeutic mouse model by regulating the balance between TH17 and iTreg cells. Targeting a glutamate-dependent metabolic pathway thus represents a new strategy for developing therapeutic agents against TH17-mediated autoimmune diseases.
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Immune cell accumulation in adipose tissue (AT) is associated with the development of AT inflammation, resulting in metabolic dysfunction. Circulating immune cell patterns may reflect immune cell accumulation in expanding AT. However, data linking human leukocytes in blood and AT is lacking. We investigated whether blood immune cell populations are associated with their counterparts in subcutaneous (scAT) or visceral AT (vAT). Flow cytometry was performed on blood, scAT and vAT from 16 lean and 29 obese men. Circulating natural killer (NK)-cells, classical monocytes and nonclassical monocytes were higher in obese individuals. vAT, but not scAT, of obese individuals contained more inflammatory CD11c+ “M1” macrophages and NK cells compared to lean individuals. Blood classical monocytes were associated with CD11c+ macrophages in vAT but not scAT. This association was unrelated to expression of the adhesion molecules CD11b and CD11c or of the chemokine receptor CX3CR1 on these monocytes. Other AT immune cells were not associated with their respective counterparts in blood. Finally, CD11c+ macrophages and CD4+ T-cells in vAT were associated with their counterparts in scAT. In conclusion, blood classical monocytes reflect CD11c+ macrophages in vAT.
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Numerous studies show that mitochondrial energy generation determines the effectiveness of immune responses. Furthermore, changes in mitochondrial function may regulate lymphocyte function in inflammatory diseases like type 2 diabetes. Analysis of lymphocyte mitochondrial function has been facilitated by introduction of 96-well format extracellular flux (XF96) analyzers, but the technology remains imperfect for analysis of human lymphocytes. Limitations in XF technology include the lack of practical protocols for analysis of archived human cells, and inadequate data analysis tools that require manual quality checks. Current analysis tools for XF outcomes are also unable to automatically assess data quality and delete untenable data from the relatively high number of biological replicates needed to power complex human cell studies. The objectives of work presented herein are to test the impact of common cellular manipulations on XF outcomes, and to develop and validate a new automated tool that objectively analyzes a virtually unlimited number of samples to quantitate mitochondrial function in immune cells. We present significant improvements on previous XF analyses of primary human cells that will be absolutely essential to test the prediction that changes in immune cell mitochondrial function and fuel sources support immune dysfunction in chronic inflammatory diseases like type 2 diabetes.
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Human CD4(+)CD25(hi)Foxp3(+)CD127(-) Treg and CD4(+)CD25(-)Foxp3(-) Tconv cell functions are governed by their metabolic requirements. Here we report a comprehensive comparative analysis between ex vivo human Treg and Tconv cells that comprises analyses of the proteomic networks in subcellular compartments. We identified a dominant proteomic signature at the metabolic level that primarily impacted the highly-tuned balance between glucose and fatty-acid oxidation in the two cell types. Ex vivo Treg cells were highly glycolytic while Tconv cells used predominantly fatty-acid oxidation (FAO). When cultured in vitro, Treg cells engaged both glycolysis and FAO to proliferate, while Tconv cell proliferation mainly relied on glucose metabolism. Our unbiased proteomic analysis provides a molecular picture of the impact of metabolism on ex vivo human Treg versus Tconv cell functions that might be relevant for therapeutic manipulations of these cells.
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Mitochondria undergo fragmentation in response to electron transport chain (ETC) poisons and mitochondrial DNA–linked disease mutations, yet how these stimuli mechanistically connect to the mitochondrial fission and fusion machinery is poorly understood. We found that the energy-sensing adenosine monophosphate (AMP)–activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. Moreover, direct pharmacological activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress. A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. Nonphosphorylatable and phosphomimetic alleles of the AMPK sites in MFF revealed that it is a key effector of AMPK-mediated mitochondrial fission.
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Brought to you by the editorial team of Cell Death and Differentiation, Cell Death and Disease is a peer-reviewed author-pays online journal in the field of translational cell death. It seeks to promote diverse and integrated areas of Experimental and Internal Medicine with its specialties, including Cancer, Immunity and Neuroscience.
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Objective: T cell inflammation plays pivotal roles in obesity-associated type 2 diabetes (T2DM). The identification of dominant sources of T cell inflammation in humans remains a significant gap in understanding disease pathogenesis. It was hypothesized that cytokine profiles from circulating T cells identify T cell subsets and T cell cytokines that define T2DM-associated inflammation. Methods: Multiplex analyses were used to quantify T cell-associated cytokines in αCD3/αCD28-stimulated PBMCs, or B cell-depleted PBMCs, from subjects with T2DM or BMI-matched controls. Cytokine measurements were subjected to multivariate (principal component and partial least squares) analyses. Flow cytometry detected intracellular TNFα in multiple immune cell subsets in the presence/absence of antibodies that neutralize T cell cytokines. Results: T cell cytokines were generally higher in T2DM samples, but Th17 cytokines are specifically important for classifying individuals correctly as T2DM. Multivariate analyses indicated that B cells support Th17 inflammation in T2DM but not control samples, while monocytes supported Th17 inflammation regardless of T2DM status. Partial least squares regression analysis indicated that both Th17 and Th1 cytokines impact %HbA1c. Conclusions: Among various T cell subsets, Th17 cells are major contributors to inflammation and hyperglycemia and are uniquely supported by B cells in obesity-associated T2DM.
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Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca) as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORγt to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO(+)CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORγt through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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AMP-activated protein kinase (AMPK) maintains energy homeostasis by suppressing cellular ATP-consuming processes and activating catabolic, ATP-producing pathways such as fatty acid oxidation (FAO). The transcription factor peroxisome proliferator-activated receptor δ (PPARδ) also affects fatty acid metabolism, stimulating the expression of genes involved in FAO. To question the interplay of AMPK and PPARδ in human macrophages we transduced primary human macrophages with lentiviral particles encoding for the constitutively active AMPKα1 catalytic subunit, followed by microarray expression analysis after treatment with the PPARδ agonist GW501516. Microarray analysis showed that co-activation of AMPK and PPARδ increased expression of FAO genes, which were validated by quantitative PCR. Induction of these FAO-associated genes was also observed upon infecting macrophages with an adenovirus coding for AMPKγ1 regulatory subunit carrying an activating R70Q mutation. The pharmacological AMPK activator A-769662 increased expression of several FAO genes in a PPARδ- and AMPK-dependent manner. Although GW501516 significantly increased FAO and reduced the triglyceride amount in very low density lipoproteins (VLDL)-loaded foam cells, AMPK activation failed to potentiate this effect, suggesting that increased expression of fatty acid catabolic genes alone may be not sufficient to prevent macrophage lipid overload.
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Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity. Copyright © 2015 Elsevier Inc. All rights reserved.
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