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An oral mixed fat load is followed by a modest anti-inflammatory adipocytokine response in overweight patients with metabolic syndrome.
We investigated the postprandial changes in plasma levels of adipocytokines in overweight patients with metabolic syndrome after an oral fat load. After an oral fat load and during a prolonged fast, blood was drawn at 0, 2, 3, 4 and 8 h for measurement of adiponectin, adipsin, cathepsin S, chemerin, hepatic growth factor, interferon-γ-inducible protein-10, leptin, macrophage chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, retinol binding protein-4, resistin, serum amyloid A1, tissue inhibitor of metalloproteinase-1 and thrombopoietin using a microbead-based Luminex assay. Area under the curves (AUC) were calculated and compared. Plasma adiponectin levels were higher after an oral fat load compared to fasting at t = 2 h (950 ± 513 vs. -1,881 ± 713 ng/ml) while the plasma levels for adipsin (-9 ± 5 vs. 16 ± 5 ng/ml), chemerin (-122 ± 35 vs. 13 ± 21 ng/ml), SAA-1 (-391 ± 213 vs. 522 ± 173 ng/ml) and TPO (-335 ± 144 vs. 622 ± 216 ng/ml) were lower after an oral fat load compared to fasting. The baseline corrected AUC for IP-10 was higher after fat load compared to fasting (median -116 pg h/ml; IQR -270 to 10 vs. -21 pg h/ml; IQR -136 to 418 (p = 0.047). In conclusion, in overweight male subjects with the metabolic syndrome, an oral fat load is accompanied with a modest anti-inflammatory response of adipose tissue-derived adipocytokines.
Altered plasma adipokine levels and in vitro adipocyte differentiation in pediatric type 1 diabetes.
CONTEXT: Type 1 diabetes (T1D) is considered a proinflammatory condition. Adipose tissue involvement seems evident because adiponectin levels correlate with disease remission and administration of leptin suppresses the low-grade systemic inflammation in mice with T1D. Whether adipose tissue involvement in T1D already occurs at a young age is yet unknown. OBJECTIVE: The aim was to explore the extent of adipokine alterations in pediatric T1D and gain more insight into the mechanisms underlying the involvement of adipose tissue. DESIGN AND PARTICIPANTS: First, plasma adipokine profiling (24 adipokines) of 20 children with onset T1D, 20 children with long-standing T1D, and 17 healthy controls was performed using a recently developed and validated multiplex immunoassay. Second, the effects of diabetic plasma factors on preadipocyte proliferation and differentiation were studied in vitro. RESULTS: In children with onset and long-standing T1D, plasma adipokine profiling showed increased levels of various adipokines acting at the crossroads of adipose tissue function and inflammation, including CCL2/monocyte chemoattractant protein-1 and the novel adipokines cathepsin S, chemerin, and tissue inhibitor of metalloproteinase-1 (P < 0.05). Furthermore, onset and long-standing diabetic plasma significantly induced preadipocyte proliferation and adipocyte differentiation in vitro (P < 0.05). Two candidate plasma factors, glucose and the saturated fatty acid palmitic acid, did not affect proliferation or adipocyte differentiation in vitro but were found to increase CCL2 (monocyte chemoattractant protein-1) secretion by adipocytes. CONCLUSIONS: The adipogenic effects of diabetic plasma in vitro and the altered adipokine levels in vivo suggest adipose tissue involvement in the low-grade inflammation associated with T1D, already in pediatric patients.
Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids.
The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. Here, we demonstrate that endogenous mesenchymal stem cells (MSCs) become activated during treatment with platinum analogs and secrete factors that protect tumor cells against a range of chemotherapeutics. Through a metabolomics approach, we identified two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), that in minute quantities induce resistance to a broad spectrum of chemotherapeutic agents. Interestingly, blocking central enzymes involved in the production of these PIFAs (cyclooxygenase-1 and thromboxane synthase) prevents MSC-induced resistance. Our findings show that MSCs are potent mediators of resistance to chemotherapy and reveal targets to enhance chemotherapy efficacy in patients.
Monocyte gene expression in childhood obesity is associated with obesity and complexity of atherosclerosis in adults.
Childhood obesity coincides with increased numbers of circulating classical CD14++CD16- and intermediate CD14++CD16+ monocytes. Monocytes are key players in the development and exacerbation of atherosclerosis, which prompts the question as to whether the monocytosis in childhood obesity contributes to atherogenesis over the years. Here, we dissected the monocyte gene expression profile in childhood obesity using an Illumina microarray platform on sorted monocytes of 35 obese children and 16 lean controls. Obese children displayed a distinctive monocyte gene expression profile compared to lean controls. Upon validation with quantitative PCR, we studied the association of the top 5 differentially regulated monocyte genes in childhood obesity with obesity and complexity of coronary atherosclerosis (SYNTAX score) in a cohort of 351 adults at risk for ischemic cardiovascular disease. The downregulation of monocyte IMPDH2 and TMEM134 in childhood obesity was also observed in obese adults. Moreover, downregulation of monocyte TMEM134 was associated with a higher SYNTAX atherosclerosis score in adults. In conclusion, childhood obesity entails monocyte gene expression alterations associated with obesity and enhanced complexity of coronary atherosclerosis in adults.
Human adipocyte extracellular vesicles in reciprocal signaling between adipocytes and macrophages.
OBJECTIVE: Extracellular vesicles (EVs) released by human adipocytes or adipose tissue (AT)-explants play a role in the paracrine interaction between adipocytes and macrophages, a key mechanism in AT inflammation, leading to metabolic complications like insulin resistance (IR) were determined. METHODS: EVs released from in vitro differentiated adipocytes and AT-explants ex vivo were characterized by electron microscopy, Western blot, multiplex adipokine-profiling, and quantified by flow cytometry. Primary monocytes were stimulated with EVs from adipocytes, subcutaneous (SCAT) or omental-derived AT (OAT), and phenotyped. Macrophage supernatant was subsequently used to assess the effect on insulin signaling in adipocytes. RESULTS: Adipocyte and AT-derived EVs differentiated monocytes into macrophages characteristic of human adipose tissue macrophages (ATM), defined by release of both pro- and anti-inflammatory cytokines. The adiponectin-positive subset of AT-derived EVs, presumably representing adipocyte-derived EVs, induced a more pronounced ATM-phenotype than the adiponectin-negative AT-EVs. This effect was more evident for OAT-EVs versus SCAT-EVs. Furthermore, supernatant of macrophages pre-stimulated with AT-EVs interfered with insulin signaling in human adipocytes. Finally, the number of OAT-derived EVs correlated positively with patients HOMA-IR. CONCLUSIONS: A possible role for human AT-EVs in a reciprocal pro-inflammatory loop between adipocytes and macrophages, with the potential to aggravate local and systemic IR was demonstrated.
Endogenous lipid antigens for invariant natural killer T cells hold the reins in adipose tissue homeostasis.
The global obesity epidemic and its associated co-morbidities, including type 2 diabetes, cardiovascular disease and certain types of cancers, have drawn attention to the pivotal role of adipocytes in health and disease. Besides their 'classical' function in energy storage and release, adipocytes interact with adipose-tissue-resident immune cells, among which are lipid-responsive invariant natural killer T (iNKT) cells. The iNKT cells are activated by lipid antigens presented by antigen-presenting cells as CD1d/lipid complexes. Upon activation, iNKT cells can rapidly secrete soluble mediators that either promote or oppose inflammation. In lean adipose tissue, iNKT cells elicit a predominantly anti-inflammatory immune response, whereas obesity is associated with declining iNKT cell numbers. Recent work showed that adipocytes act as non-professional antigen-presenting cells for lipid antigens. Here, we discuss endogenous lipid antigen processing and presentation by adipocytes, and speculate on how these lipid antigens, together with 'environmental factors' such as tissue/organ environment and co-stimulatory signals, are able to influence the fate of adipose-tissue-resident iNKT cells, and thereby the role of these cells in obesity and its associated pathologies.
Vitamin D deficiency in childhood obesity is associated with high levels of circulating inflammatory mediators, and low insulin sensitivity.
HYPOTHESIS: Childhood obesity is accompanied by low-grade systemic inflammation, which contributes to the development of insulin resistance and cardiovascular complications later in life. As vitamin D exhibits profound immunomodulatory functions and vitamin D deficiency is highly prevalent in childhood obesity, we hypothesized that vitamin D deficiency in childhood obesity coincides with enhanced systemic inflammation and reduced insulin sensitivity. METHODS: In a cross-sectional study of 64 obese and 32 healthy children aged 6-16 years, comprehensive profiling of 32 circulating inflammatory mediators was performed, together with assessment of 25-hydroxyvitamin D (25(OH)D) levels and measures for insulin sensitivity. RESULTS: Severe vitamin D insufficiency, which is further referred to as vitamin D deficiency, was defined as a 25(OH)D level ≤37.5 nmol l(-1), and was highly prevalent in obese (56%) versus healthy control children (16%). Throughout the study, 25(OH)D-deficient children were compared with the other children, including 25(OH)D insufficient (37.5-50 nmol l(-1)) and 25(OH)D sufficient children (≥50 nmol l(-1)). First, 25(OH)D-deficient obese children showed a lower insulin sensitivity than other obese children, as measured by a lower quantitative insulin sensitivity check index. Second, the association between 25(OH)D deficiency and insulin resistance in childhood obesity was confirmed with multiple regression analysis. Third, 25(OH)D-deficient obese children showed higher levels of the inflammatory mediators cathepsin S, chemerin and soluble vascular adhesion molecule (sVCAM), compared with the other obese children. Finally, hierarchical cluster analysis revealed an over-representation of 25(OH)D deficiency in obese children expressing inflammatory mediator clusters with high levels of cathepsin S, sVCAM and chemerin. CONCLUSION: 25(OH)D deficiency in childhood obesity was associated with enhanced systemic inflammation and reduced insulin sensitivity. The high cathepsin S and sVCAM levels may reflect activation of a pro-inflammatory, pro-diabetic and atherogenic pathway, which could be inhibited by vitamin D supplementation.
Immunometabolic Activation of Invariant Natural Killer T Cells.
Invariant natural killer T (iNKT) cells are lipid-reactive T cells with profound immunomodulatory potential. They are unique in their restriction to lipid antigens presented in CD1d molecules, which underlies their role in lipid-driven disorders such as obesity and atherosclerosis. In this review, we discuss the contribution of iNKT cell activation to immunometabolic disease, metabolic programming of lipid antigen presentation, and immunometabolic activation of iNKT cells. First, we outline the role of iNKT cells in immunometabolic disease. Second, we discuss the effects of cellular metabolism on lipid antigen processing and presentation to iNKT cells. The synthesis and processing of glycolipids and other potential endogenous lipid antigens depends on metabolic demand and may steer iNKT cells toward adopting a Th1 or Th2 signature. Third, external signals such as toll-like receptor ligands, adipokines, and cytokines modulate antigen presentation and subsequent iNKT cell responses. Finally, we will discuss the relevance of metabolic programming of iNKT cells in human disease, focusing on their role in disorders such as obesity and atherosclerosis. The critical response to metabolic changes places iNKT cells at the helm of immunometabolic disease.
Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children.
BACKGROUND: Childhood obesity prevalence has increased worldwide and is an important risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). The production of inflammatory adipokines by obese adipose tissue contributes to the development of T2D and CVD. While levels of circulating adipokines such as adiponectin and leptin have been established in obese children and adults, the expression of adiponectin and leptin receptors on circulating immune cells can modulate adipokine signalling, but has not been studied so far. Here, we aim to establish the expression of adiponectin and leptin receptors on circulating immune cells in obese children pre and post-lifestyle intervention compared to normal weight control children. METHODS: 13 obese children before and after a 1-year lifestyle intervention were compared with an age and sex-matched normal weight control group of 15 children. Next to routine clinical and biochemical parameters, circulating adipokines were measured, and flow cytometric analysis of adiponectin receptor 1 and 2 (AdipoR1, AdipoR2) and leptin receptor expression on peripheral blood mononuclear cell subsets was performed. RESULTS: Obese children exhibited typical clinical and biochemical characteristics compared to controls, including a higher BMI-SD, blood pressure and circulating leptin levels, combined with a lower insulin sensitivity index (QUICKI). The 1-year lifestyle intervention resulted in stabilization of their BMI-SD. Overall, circulating leukocyte subsets showed distinct adipokine receptor expression profiles. While monocytes expressed high levels of all adipokine receptors, NK and iNKT cells predominantly expressed AdipoR2, and B-lymphocytes and CD4+ and CD8+ T-lymphocyte subsets expressed AdipoR2 as well as leptin receptor. Strikingly though, leukocyte subset numbers and adipokine receptor expression profiles were largely similar in obese children and controls. Obese children showed higher naïve B-cell numbers, and pre-intervention also higher numbers of immature transition B-cells and intermediate CD14++CD16+ monocytes combined with lower total monocyte numbers, compared to controls. Furthermore, adiponectin receptor 1 expression on nonclassical CD14+CD16++ monocytes was consistently upregulated in obese children pre-intervention, compared to controls. However, none of the differences in leukocyte subset numbers and adipokine receptor expression profiles between obese children and controls remained significant after multiple testing correction. CONCLUSIONS: First, the distinct adipokine receptor profiles of circulating leukocyte subsets may partly explain the differential impact of adipokines on leukocyte subsets. Second, the similarities in adipokine receptor expression profiles between obese children and normal weight controls suggest that adipokine signaling in childhood obesity is primarily modulated by circulating adipokine levels, instead of adipokine receptor expression.
CD1d-mediated presentation of endogenous lipid antigens by adipocytes requires microsomal triglyceride transfer protein.
Obesity-induced adipose tissue (AT) dysfunction results in a chronic low-grade inflammation that predisposes to the development of insulin resistance and type 2 diabetes. During the development of obesity, the AT-resident immune cell profile alters to create a pro-inflammatory state. Very recently, CD1d-restricted invariant (i) natural killer T (NKT) cells, a unique subset of lymphocytes that are reactive to so called lipid antigens, were implicated in AT homeostasis. Interestingly, recent data also suggest that human and mouse adipocytes can present such lipid antigens to iNKT cells in a CD1d-dependent fashion, but little is known about the lipid antigen presentation machinery in adipocytes. Here we show that CD1d, as well as the lipid antigen loading machinery genes pro-saposin (Psap), Niemann Pick type C2 (Npc2), α-galactosidase (Gla), are up-regulated in early adipogenesis, and are transcriptionally controlled by CCAAT/enhancer-binding protein (C/EBP)-β and -δ. Moreover, adipocyte-induced Th1 and Th2 cytokine release by iNKT cells also occurred in the absence of exogenous ligands, suggesting the display of endogenous lipid antigen-D1d complexes by 3T3-L1 adipocytes. Furthermore, we identified microsomal triglyceride transfer protein, which we show is also under the transcriptional regulation of C/EBPβ and -δ, as a novel player in the presentation of endogenous lipid antigens by adipocytes. Overall, our findings indicate that adipocytes can function as non-professional lipid antigen presenting cells, which may present an important aspect of adipocyte-immune cell communication in the regulation of whole body energy metabolism and immune homeostasis.
The dorsal posterior insula is not an island in pain but subserves a fundamental role - Response to: "Evidence against pain specificity in the dorsal posterior insula" by Davis et al.
An interesting and valuable discussion has arisen from our recent article (Segerdahl, Mezue et al., 2015) and we are pleased here to have the opportunity to expand on the various points we made. Equally important, we wish to correct several important misunderstandings that were made by Davis and colleagues that possibly contributed to their concerns about power when assessing our paper (e.g. actual subject numbers used in control experiment and the reality of the signal-to-noise and sampling of the multi-TI technique we employed). Here, we clarify the methods and analysis plus discuss how we interpret the data in the Brief Communication noting that the extrapolation and inferences made by Davis and colleagues are not consistent with our report or necessarily, in our opinion, what the data supports. We trust this reassures the F1000Research readership regarding the robustness of our results and what we actually concluded in the paper regarding their possible meaning. We are pleased, though, that Davis and colleagues have used our article to raise an important discussion around pain perception, and here offer some further insights towards that broader discussion.
Pain in multiple sclerosis: a systematic review of neuroimaging studies.
INTRODUCTION: While pain in multiple sclerosis (MS) is common, in many cases the precise mechanisms are unclear. Neuroimaging studies could have a valuable role in investigating the aetiology of pain syndromes. The aim of this review was to synthesise and appraise the current literature on neuroimaging studies of pain syndromes in MS. METHODS: We systematically searched PubMed and Scopus from their inception dates to the 2nd of April 2013. Studies were selected by predefined inclusion and exclusion criteria. Methodological quality was appraised. Descriptive statistical analysis was conducted. RESULTS: We identified 38 studies of variable methodology and quality. All studies but one used conventional structural magnetic resonance imaging, and the majority reported a positive association between location of demyelinating lesions and specific neuropathic pain syndromes. Most investigated headache and facial pain, with more common pain syndromes such as limb pain being relatively understudied. We identified a number of methodological concerns, which along with variable study design and reporting limit our ability to synthesise data. Higher quality studies were however less likely to report positive associations of lesion distribution to pain syndromes. CONCLUSIONS: Further high quality hypothesis-driven neuroimaging studies of pain syndromes in MS are required to clarify pain mechanisms, particularly for the commonest pain syndromes.
Dissociable neural mechanisms underlying the modulation of pain and anxiety? An FMRI pilot study.
The down-regulation of pain through beliefs is commonly discussed as a form of emotion regulation. In line with this interpretation, the analgesic effect has been shown to co-occur with reduced anxiety and increased activity in the ventrolateral prefrontal cortex (VLPFC), which is a key region of emotion regulation. This link between pain and anxiety modulation raises the question whether the two effects are rooted in the same neural mechanism. In this pilot fMRI study, we compared the neural basis of the analgesic and anxiolytic effect of two types of threat modulation: a "behavioral control" paradigm, which involves the ability to terminate a noxious stimulus, and a "safety signaling" paradigm, which involves visual cues that signal the threat (or absence of threat) that a subsequent noxious stimulus might be of unusually high intensity. Analgesia was paralleled by VLPFC activity during behavioral control. Safety signaling engaged elements of the descending pain control system, including the rostral anterior cingulate cortex that showed increased functional connectivity with the periaqueductal gray and VLPFC. Anxiety reduction, in contrast, scaled with dorsolateral prefrontal cortex activation during behavioral control but had no distinct neural signature during safety signaling. Our pilot data therefore suggest that analgesic and anxiolytic effects are instantiated in distinguishable neural mechanisms and differ between distinct stress- and pain-modulatory approaches, supporting the recent notion of multiple pathways subserving top-down modulation of the pain experience. Additional studies in larger cohorts are needed to follow up on these preliminary findings.
Phantom pain is associated with preserved structure and function in the former hand area.
Phantom pain after arm amputation is widely believed to arise from maladaptive cortical reorganization, triggered by loss of sensory input. We instead propose that chronic phantom pain experience drives plasticity by maintaining local cortical representations and disrupting inter-regional connectivity. Here we show that, while loss of sensory input is generally characterized by structural and functional degeneration in the deprived sensorimotor cortex, the experience of persistent pain is associated with preserved structure and functional organization in the former hand area. Furthermore, consistent with the isolated nature of phantom experience, phantom pain is associated with reduced inter-regional functional connectivity in the primary sensorimotor cortex. We therefore propose that contrary to the maladaptive model, cortical plasticity associated with phantom pain is driven by powerful and long-lasting subjective sensory experience, such as triggered by nociceptive or top-down inputs. Our results prompt a revisiting of the link between phantom pain and brain organization.
Pain, decisions, and actions: a motivational perspective.
Because pain signals potential harm to the organism, it immediately attracts attention and motivates decisions and action. However, pain is also subject to motivations-an aspect that has led to considerable changes in our understanding of (chronic) pain over the recent years. The relationship between pain and motivational states is therefore clearly bidirectional. This review provides an overview on behavioral and neuroimaging studies investigating motivational aspects of pain. We highlight recent insights into the modulation of pain through fear and social factors, summarize findings on the role of pain in fear conditioning, avoidance learning and goal conflicts and discuss evidence on pain-related cognitive interference and motivational aspects of pain relief.
An fMRI study exploring the overlap and differences between neural representations of physical and recalled pain.
Implementing a recall paradigm without hypnosis, we use functional MRI (fMRI) to explore and compare nociceptive and centrally-driven pain experiences. We posit that a trace of a recent nociceptive event can be used to create sensory-re-experiencing of pain that can be qualified in terms of intensity and vividness. Fifteen healthy volunteers received three levels of thermal stimuli (warm, low pain and high pain) and subsequently were asked to recall and then rate this experience. Neuroimaging results reveal that recalling a previous sensory experience activates an extensive network of classical pain processing structures except the contralateral posterior insular cortex. Nociceptive-specific activation of this structure and the rated intensity difference between physical and recalled pain events allow us to investigate the link between the quality of the original nociceptive stimulus and the mental trace, as well as the differences between the accompanying neural responses. Additionally, by incorporating the behavioural ratings, we explored which brain regions were separately responsible for generating either an accurate or vivid recall of the physical experience. Together, these observations further our understanding of centrally-mediated pain experiences and pain memory as well as the potential relevance of these factors in the maintenance of chronic pain.