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BACKGROUND: Obesity is associated with low-grade inflammation and increased intestinal permeability (IP). The Brazil nut (BN) (Bertholletia excelsa H.B.K.) appears to be a promising dietary intervention to control inflammation by enhancing antioxidant defenses. OBJECTIVES: We aimed to assess the effect of daily BN consumption on inflammatory biomarkers and IP in the context of an energy-restricted intervention. Furthermore, we evaluated the correlation between the changes in these inflammatory markers and the changes in serum selenium and IP. METHODS: In this 8-wk nonrandomized controlled trial, 56 women with overweight or obesity were allocated into 2 groups, both following an energy-restricted diet (-500 kcal/d). The control group (CO) consumed a nut-free diet, while the BN group consumed 8 g BN/d, providing 347.2 µg selenium (Se). Inflammatory cytokines were analyzed in plasma and Se in serum. IP was assessed using the lactulose/mannitol test (LM ratio). RESULTS: Forty-six women completed the intervention. Both groups achieved similar energy restriction (CO Δ= -253.7 ± 169.4 kcal/d; BN Δ= -265.8 ± 141.8 kcal/d) and weight loss (CO Δ= -2.5 ± 0.5 kg; BN Δ= -3.5 ± 0.5 kg). The BN group showed lower values of C-reactive protein, tumor necrosis factor, interleukin (IL)1-ß, IL-8, percentage lactulose excretion, and LM ratio than the CO group. Additionally, changes in serum Se concentration were predictive of changes in IL-8 concentration (ß: -0.054; adjusted R2: 0.100; 95% confidence interval [CI]: -0.100; -0.007; P = 0.025), and changes in IL-8 were predictive of changes in the LM ratio (ß: 0.006; adjusted R2: 0.101; 95% CI: 0.001, 0.011; P = 0.024). CONCLUSIONS: Regular intake of BNs can be a promising complementary dietary strategy for controlling low-grade inflammation and improving IP in women with overweight/obesity undergoing energy-restricted treatment. However, the effects of BNs seem to be Se status-dependent. This trial was registered at the Brazilian Registry of Clinical Trials (ReBEC: https://ensaiosclinicos.gov.br/rg/RBR-3ntxrm/.
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Bertholletia , Biomarcadores , Obesidade , Sobrepeso , Selênio , Humanos , Feminino , Bertholletia/química , Adulto , Obesidade/dietoterapia , Obesidade/sangue , Biomarcadores/sangue , Sobrepeso/dietoterapia , Sobrepeso/sangue , Pessoa de Meia-Idade , Selênio/sangue , Inflamação/sangue , Restrição Calórica , Permeabilidade , Brasil , Nozes , Citocinas/sangue , Função da Barreira IntestinalRESUMO
Glycolipid metabolic disorders (GLMDs) are various metabolic disorders resulting from dysregulation in glycolipid levels, consequently leading to an increased risk of obesity, diabetes, liver dysfunction, neuromuscular complications, and cardiorenal vascular diseases (CRVDs). In patients with GLMDs, excess caloric intake and a lack of physical activity may contribute to oxidative stress (OxS) and systemic inflammation. This study aimed to review the connection between GLMD, OxS, metainflammation, and the onset of CRVD. GLMD is due to various metabolic disorders causing dysfunction in the synthesis, breakdown, and absorption of glucose and lipids in the body, resulting in excessive ectopic accumulation of these molecules. This is mainly due to neuroendocrine dysregulation, insulin resistance, OxS, and metainflammation. In GLMD, many inflammatory markers and defense cells play a vital role in related tissues and organs, such as blood vessels, pancreatic islets, the liver, muscle, the kidneys, and adipocytes, promoting inflammatory lesions that affect various interconnected organs through their signaling pathways. Advanced glycation end products, ATP-binding cassette transporter 1, Glucagon-like peptide-1, Toll-like receptor-4, and sphingosine-1-phosphate (S1P) play a crucial role in GLMD since they are related to glucolipid metabolism. The consequences of this is system organ damage and increased morbidity and mortality.
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Objective. Blood C-reactive protein (CRP) and the electrical bioimpedance spectroscopy (EBIS) variables phase angle (PhA) and impedance ratio (IR) have been proposed as biomarkers of metainflammation in overweight/obesity. CRP involves taking blood samples, while PhA and IR imply a less-than-2-minute-non-invasive procedure. In this study, values for these variables and percent body fat mass (PBFM) were obtained and compared before and immediately after a colon cleansing protocol (CCP), aimed at modulating intestinal microbiota and reducing metainflammation, as dysbiosis and the latter are intrinsically related, as well as along a period of 8 weeks after it.Approach. 20 female volunteers (20.9-24.9 years old) participated: 12 in an overweight group (OG), and 8 in a lean group (LG). TheOGwas divided in two subgroups (n= 6, each): control (CSG) and experimental (ESG). TheESGunderwent a 6-day CCP at week 2, while 5 volunteers in theCSGunderwent it at week 9.Main results.Pre/post-CCP mean values for the variables in theOGwere: PBFM (34.3/31.3%), CRP (3.7/0.6 mg dl-1), PhA (6.9/7.5°) and IR*10 (0.78/0.77). CalculatedR2correlation factors among these variables are all above 0.89. The favourable changes first seen in theESGwere still present 8 weeks after the CCP.Significance.(a) the CCP drastically lowers meta-inflammation, (b) EBIS can be used to measure metainflammation, before and after treatment, (c) for microbiota modulation, CCP could be a good alternative to more drastic procedures like faecal microbiota transplantation; (d) reestablishing eubiosis by CCP could be an effective coadjutant in the treatment of overweight young adult women.
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Biomarcadores , Colo , Impedância Elétrica , Inflamação , Sobrepeso , Humanos , Feminino , Biomarcadores/sangue , Biomarcadores/metabolismo , Adulto Jovem , Colo/metabolismo , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análiseRESUMO
BACKGROUND: Obesity, dyslipidemia, and low-grade inflammatory state form a triad of self-sustaining metabolic dysfunction. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy is a simple, rapid, and non-destructive technique that generates spectral fingerprints of biomolecules that can be correlated with metabolic changes. We verified the efficiency of ATR-FTIR spectroscopy in blood plasma (n = 74) to discriminate the types of dyslipidemias and suggest metabolic inflammatory changes. METHODS: Principal Component Analysis (PCA) was performed on the biochemical and anthropometric data to verify whether the dyslipidemia types share a similar biochemical profile plausible of discrimination in chemometric modeling. To discriminate the types of dyslipidemias based on spectral data, Orthogonal Partial Least-Squares Discriminant Analysis (OPLS-DA) was used and validated with leave-one-out cross-validation. RESULTS: Although no significant difference was obtained between the types of dyslipidemia and normal subjects by CRP, leptin, and cfDNA, there was a significant difference between normal subjects vs combined hyperlipidemia (CH) + hypercholesterolemia (HCL) + hypertriglyceridemia (HTG) (p < 0.05) by the 1245 cm-1 peak [νas(PO2-)] (possible indication of chronic inflammation by increased cfDNA). The area under the curve of the region between 1770 and 1720 cm-1 was significantly increased for CH in relation to other dyslipidemias and normal subjects. Furthermore, there were significant differences for the main representative peaks of lipids, proteins, carbohydrates, and nucleic acids between the types of dyslipidemias and between the types of dyslipidemias and normal subjects. The OPLS-DA model achieved 100 % accuracy with 1 latent variable and Standard Error of Cross-Validation (SECV) < 0.004 for all types of dyslipidemia and the control group. CONCLUSIONS: Our results suggest that ATR-FTIR spectroscopy associated with chemometric modeling is a plausible applicant for screening the types of dyslipidemias. However, more extensive studies should be conducted to verify the real applicability in clinical analysis laboratories or medical clinics.
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Ácidos Nucleicos Livres , Dislipidemias , Humanos , Proteínas Mutadas de Ataxia Telangiectasia , Biomarcadores , Quimiometria , Análise Discriminante , Dislipidemias/diagnóstico , Análise dos Mínimos Quadrados , Lipídeos , Análise Multivariada , Análise de Componente Principal , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Inflamação/diagnósticoRESUMO
Dyslipidemia is described as a hallmark of metabolic syndrome, promoting a stage of metabolic inflammation (metainflammation) that could lead to misbalances in energetic metabolism, contributing to insulin resistance, and modifying intracellular cholesterol pathways and the renin-angiotensin system (RAS) in pancreatic islets. Low-density lipoprotein (LDL) hypercholesterolemia could disrupt the tissue communication between Langerhans ß-cells and hepatocytes, wherein extracellular vesicles (EVs) are secreted by ß-cells, and exposition to LDL can impair these phenomena. ß-cells activate compensatory mechanisms to maintain insulin and metabolic homeostasis; therefore, the work aimed to characterize the impact of LDL on ß-cell cholesterol metabolism and the implication on insulin secretion, connected with the regulation of cellular communication mediated by EVs on hepatocytes. Our results suggest that ß-cells can endocytose LDL, promoting an increase in de novo cholesterol synthesis targets. Notably, LDL treatment increased mRNA levels and insulin secretion; this hyperinsulinism condition was associated with the transcription factor PDX-1. However, a compensatory response that maintains basal levels of intracellular calcium was described, mediated by the overexpression of calcium targets PMCA1/4, SERCA2, and NCX1, together with the upregulation of the unfolded protein response (UPR) through the activation of IRE1 and PERK arms to maintain protein homeostasis. The LDL treatment induced metainflammation by IL-6, NF-κB, and COX-2 overexpression. Furthermore, LDL endocytosis triggered an imbalance of the RAS components. LDL treatment increased the intracellular levels of cholesterol on lipid droplets; the adaptive ß-cell response was portrayed by the overexpression of cholesterol transporters ABCA1 and ABCG1. Therefore, lipotoxicity and hyperinsulinism induced by LDL were regulated by the natural compound auraptene, a geranyloxyn coumarin modulator of cholesterol-esterification by ACAT1 enzyme inhibition. EVs isolated from ß-cells impaired insulin signaling via mTOR/p70S6Kα in hepatocytes, a phenomenon regulated by auraptene. Our results show that LDL overload plays a novel role in hyperinsulinism, mechanisms associated with a dysregulation of intracellular cholesterol, lipotoxicity, and the adaptive UPR, which may be regulated by coumarin-auraptene; these conditions explain the affectations that occur during the initial stages of insulin resistance.
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Type 2 diabetes (T2D) is a metabolic disease characterized by increased inflammation, NOD-like receptors (NLRs) activation and gut dysbiosis. Our research group has recently reported that intestinal Th17 response limits gut dysbiosis and LPS translocation to visceral adipose tissue (VAT), protecting against metabolic syndrome. However, whether NOD2 receptor contributes intestinal Th17 immunity, modulates dysbiosis-driven metabolic tissue inflammation, and obesity-induced T2D remain poorly understood. In this context, we observed that mice lacking NOD2 fed a high-fat diet (HFD) display severe obesity, exhibit greater adiposity, and more hepatic steatosis compared to HFD-fed wild-type (WT) mice. In addition, they develop increased hyperglycemia, worsening of glucose intolerance, and insulin resistance. Notably, the deficiency of NOD2 causes a deviation from M2 macrophage and regulatory T cells (Treg) to M1 macrophage and mast cells into VAT compared to WT mice fed HFD. An imbalance was also observed in Th17/Th1 cell populations, with reduced IL-17 and IL-22 gene expression in the mesenteric lymph nodes (MLNs) and ileum, respectively, of NOD2-deficient mice fed HFD. 16S rRNA sequencing indicates lower richness, alpha diversity, and a depletion of Allobaculum, Lactobacillus, and enrichment with Bacteroides genera in these mice compared to HFD-fed WT mice. These alterations were associated with disrupted tight-junctions expression, augmented serum LPS, and bacterial translocation into VAT. Overall, NOD2 activation is required for a protective Th17 over Th1 immunity in the gut, which seems to decrease gram-negative bacteria outgrowth in gut microbiota, attenuating the endotoxemia, metainflammation, and protecting against obesity-induced T2D.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Proteína Adaptadora de Sinalização NOD2/deficiência , Animais , Biomarcadores , Dieta Hiperlipídica , Modelos Animais de Doenças , Microbioma Gastrointestinal/imunologia , Perfilação da Expressão Gênica , Glucose/metabolismo , Imuno-Histoquímica , Insulina/sangue , Insulina/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Ilhotas Pancreáticas/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Permeabilidade , Transdução de SinaisRESUMO
Ceramides are key lipids in energetic-metabolic pathways and signaling cascades, modulating critical physiological functions in cells. While synthesis of ceramides is performed in endoplasmic reticulum (ER), which is altered under overnutrition conditions, proteins associated with ceramide metabolism are located on membrane arrangement of mitochondria and ER (MAMs). However, ceramide accumulation in meta-inflammation, condition that associates obesity with a chronic low-grade inflammatory state, favors the deregulation of pathways such as insulin signaling, and induces structural rearrangements on mitochondrial membrane, modifying its permeability and altering the flux of ions and other molecules. Considering the wide biological processes in which sphingolipids are implicated, they have been associated with diseases that present abnormalities in their energetic metabolism, such as breast cancer. In this sense, sphingolipids could modulate various cell features, such as growth, proliferation, survival, senescence, and apoptosis in cancer progression; moreover, ceramide metabolism is associated to chemotherapy resistance, and regulation of metastasis. Cellâ»cell communication mediated by exosomes and lipoproteins has become relevant in the transport of several sphingolipids. Therefore, in this work we performed a comprehensive analysis of the state of the art about the multifaceted roles of ceramides, specifically the deregulation of ceramide metabolism pathways, being a key factor that could modulate neoplastic processes development. Under specific conditions, sphingolipids perform important functions in several cellular processes, and depending on the preponderant species and cellular and/or tissue status can inhibit or promote the development of metabolic and potentially breast cancer disease.
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Neoplasias da Mama/etiologia , Neoplasias da Mama/metabolismo , Metabolismo dos Carboidratos , Ceramidas/metabolismo , Animais , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Retículo Endoplasmático/metabolismo , Transição Epitelial-Mesenquimal , Exossomos/metabolismo , Feminino , Humanos , Inflamação/complicações , Inflamação/metabolismo , Redes e Vias Metabólicas , Mitocôndrias/metabolismo , Metástase Neoplásica , Transdução de Sinais , Esfingolipídeos/metabolismoRESUMO
Food additives are compounds used in order to improve food palatability, texture, and shelf life. Despite a significant effort to assure safety of use, toxicological analysis of these substances, generally, rely on their direct toxicity to target organs (liver and kidney) or their genotoxic effects. Much less attention is paid to the effects of these compounds on cells of the immune system. This is of relevance given that metabolic dysregulation and obesity have a strong immune-mediated component. Obese individuals present a state of chronic low-grade inflammation that contributes to the establishment of insulin resistance and other metabolic abnormalities known as the metabolic syndrome. Obesity and metabolic syndrome are currently recognized as worldwide epidemics that pose a profound socioeconomic impact and represent a concern to public health. Cells of the immune system contribute to both the maintenance of "lean homeostasis" and the metabolic dysregulation observed in obese individuals. Although much attention has been drawn in the past decades to obesity and metabolic syndrome as a result of ingesting highly processed food containing large amounts of fat and simple sugars, mounting evidence suggest that food additives may also be important contributors to metabolic derangement. Herein, we review pieces of evidence from the literature showing that food additives have relevant effects on cells of the immune system that could contribute to immune-mediated metabolic dysregulation. Considering their potential to predispose individuals to develop obesity and metabolic syndrome, their use should be taken with caution or maybe revisited.
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OBJECTIVE: Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. METHODS: We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Pparδ/Pparγ) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Pparδ/Pparγ genes (downstream effectors of Stat6). Palmitic acid (PA) and ß-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. RESULTS: Profiling of genes regulated by Il-4 or Pparδ/Pparγ agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Pparδ/Pparγ increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6-/- macrophages and to a lesser extent, in Pparδ/γ-/- macrophages. In concert, ß-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Pparδ/γ-/- or Stat6-/- mice. CONCLUSIONS: Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state.