Relationship between Innate Immune Response Toll-Like Receptor 4 (TLR-4) and the Pathophysiological Process of Obesity Cardiomyopathy. / Relação entre Resposta Imune Inata do Receptor Toll-Like-4 (TLR-4) e o Processo Fisiopatológico da Cardiomiopatia da Obesidade.

BACKGROUND: Obesity is a chronic low-grade inflammation condition related to cardiac disorders. However, the mechanism responsible for obesity-related cardiac inflammation is unclear. The toll-like receptor 4 (TLR-4) belongs to a receptor of the transmembrane family responsible for the immune response whose activation stimulates the production of proinflammatory cytokines. OBJECTIVE: To test whether the activation of the TLR-4 receptor participates in the obesity cardiomyopathy process, due to cytokine production through NF-ĸB activation. METHODS: Male Wistar rats were randomized into two groups: the control group (C, n= 8 animals) that received standard diet/water and the obese group (OB, n= 8 animals) that were fed a high sugar-fat diet and water plus 25% of sucrose for 30 weeks. Nutritional analysis: body weight, adiposity index, food, water, and caloric intake. Obesity-related disorders analysis: plasma glucose, uric acid and triglycerides, HOMA-IR, systolic blood pressure, TNF-α in adipose tissue. Cardiac analysis included: TLR-4 and NF-ĸB protein expression, TNF-α and IL-6 levels. Comparison by unpaired Student's t-test or Mann- Whitney test with a p-value < 0.05 as statistically significant. RESULTS: The OB group showed obesity, high glucose, triglycerides, uric acid, HOMA, systolic blood pressure, and TNF-α in adipose tissue. OB group presented cardiac remodeling and diastolic dysfunction. TLR-4 and NF-ĸB expression and cytokine levels were higher in OB. CONCLUSION: Our findings conclude that, in an obesogenic condition, the inflammation derived from cardiac TLR-4 activation can be a mechanism able to lead to remodeling and cardiac dysfunction.

FUNDAMENTO: A obesidade é uma condição inflamatória crônica de baixo grau relacionada a distúrbios cardíacos. No entanto, o mecanismo responsável pela inflamação cardíaca relacionada à obesidade não é claro. O receptor do tipo toll 4 (TLR-4) pertence a um receptor da família das transmembranas, responsável pela resposta imune, cuja ativação estimula a produção de citocinas pró-inflamatórias. OBJETIVO: Testar se a ativação do receptor TLR-4 participa do processo de cardiomiopatia da obesidade, devido à produção de citocinas por meio da ativação do NF-ĸB. MÉTODOS: Ratos Wistar machos foram randomizados em dois grupos: o grupo controle (C, n = 8 animais) que recebeu dieta padrão/água e o grupo obeso (OB, n = 8 animais) que foi alimentado com dieta rica em açúcar e gordura e água mais 25% de sacarose por 30 semanas. Análise nutricional: peso corporal, índice de adiposidade, alimentos, água e ingestão calórica. Análise de distúrbios relacionados à obesidade: glicose plasmática, ácido úrico e triglicerídeos, HOMA-IR, pressão arterial sistólica, TNF-α no tecido adiposo. A análise cardíaca incluiu: expressão das proteínas TLR-4 e NF-ĸB, níveis de TNF-α e IL-6. Comparação pelo teste t de Student não pareado ou teste de Mann-Whitney com um valor de p <0,05 como estatisticamente significativo. RESULTADOS: O grupo OB apresentou obesidade, glicose elevada, triglicerídeos, ácido úrico, HOMA, pressão arterial sistólica e TNF-α no tecido adiposo. O grupo OB apresentou remodelação cardíaca e disfunção diastólica. A expressão de TLR-4 e NF-ĸB e os níveis de citocinas foram maiores em OB. CONCLUSÃO: Nossos achados concluem que, em uma condição obesogênica, a inflamação derivada da ativação do TLR-4 cardíaco pode ser um mecanismo capaz de levar à remodelação e disfunção cardíaca.

Antioxidant and anti-inflammatory properties of gamma- oryzanol attenuates insulin resistance by increasing GLUT- 4 expression in skeletal muscle of obese animals.

BACKGROUND: Skeletal muscle is the most important organ for whole-body glucose homeostasis. However, it has been suggested that obesity-related inflammation could be involved in insulin resistance and diabetes mellitus type 2 (DM2) development due several mechanisms, among them, the reduced expression of the glucose transporter type 4 (GLUT-4). Gamma-oryzanol (γOz) is a compound present in the whole grain of rice that presents anti-inflammatory and antioxidant activities. The aim of this study was to verify if the effect antioxidant and anti-inflammatory of yOz attenuate insulin resistance in skeletal muscle of obese rats by increasing GLUT- 4 expression. METHODS: Male Wistar rats (±187 g) were initially randomly distributed into 2 experimental groups (control, n = 6, and high sugar-fat diet (HSF), n = 12) for 20 weeks. At week 20th of this study, once obesity and insulin resistance were detected in the HSF group, animals were divided to begin the treatment with γOz or continue receiving HSF for 10 more weeks. At the end it was analyzed nutritional, metabolic, inflammatory and oxidative stress parameters and GLUT-4 protein expression. RESULTS: The treatment improved insulin resistance, reduced inflammation, increased antioxidant response and GLUT-4 expression. CONCLUSION: It is possible to conclude that the antioxidant and anti-inflammatory activity of yOz attenuates insulin resistance by increasing GLUT-4 expression in skeletal muscle of obese animals.

Gamma-oryzanol as a potential modulator of oxidative stress and inflammation via PPAR-y in adipose tissue: a hypothetical therapeutic for cytokine storm in COVID-19?

The literature has reported a higher prevalence of negative clinical outcomes due to Coronavirus disease 19 (COVID-19) in obese individuals. This can be explained by the cytokine storm, result from the cytokine production from both obesity and viral infection. Gamma-oryzanol (γOz) is a compound with anti-inflammatory and antioxidant activities. However, little is known about the γOz action as a possible agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). The aim of this study was to test the hypothesis that γOz attenuates the cytokine storm by stimulating PPAR-γ in the adipose tissue. METHODS: Male Wistar rats were randomly divided into three experimental groups and fed ad libitum for 30 weeks with control diet (C, n = 6), high sugar-fat diet (HSF, n = 6) or high sugar-fat diet + Î³Oz (HSF + Î³Oz, n = 6). HSF groups also received water + sucrose (25%). The γOz dose was 0.5% in the chow. Evaluation in animals included caloric intake, body weight, adiposity index, plasma triglycerides, and HOMA-IR. In adipose tissue was evaluated: PPAR-γ gene and protein expression, inflammatory and oxidative stress parameters, and histological analysis. RESULTS: Adipose tissue dysfunction was observed in HSF group, which presented remarkable PPAR-γ underexpression and increased levels of cytokines, other inflammatory markers and oxidative stress. The γOz treatment prevented adipose tissue dysfunction and promoted PPAR-γ overexpression. CONCLUSION: Natural compounds as γOz can be considered a coadjutant therapy to prevent the cytokine storm in COVID-19 patients with obesity conditions.

Relação entre resposta imune inata do receptor toll-like-4 (TLR-4) e o processo fisiopatológico da cardiomiopatia da obesidade / Relationship between innate immune response toll-like receptor 4 (TLR-4) and the pathophysiological process of obesity cardiomyopathy

Resumo Fundamento A obesidade é uma condição inflamatória crônica de baixo grau relacionada a distúrbios cardíacos. No entanto, o mecanismo responsável pela inflamação cardíaca relacionada à obesidade não é claro. O receptor do tipo toll 4 (TLR-4) pertence a um receptor da família das transmembranas, responsável pela resposta imune, cuja ativação estimula a produção de citocinas pró-inflamatórias. Objetivo Testar se a ativação do receptor TLR-4 participa do processo de cardiomiopatia da obesidade, devido à produção de citocinas por meio da ativação do NF-ĸB. Métodos Ratos Wistar machos foram randomizados em dois grupos: o grupo controle (C, n = 8 animais) que recebeu dieta padrão/água e o grupo obeso (OB, n = 8 animais) que foi alimentado com dieta rica em açúcar e gordura e água mais 25% de sacarose por 30 semanas. Análise nutricional: peso corporal, índice de adiposidade, alimentos, água e ingestão calórica. Análise de distúrbios relacionados à obesidade: glicose plasmática, ácido úrico e triglicerídeos, HOMA-IR, pressão arterial sistólica, TNF-α no tecido adiposo. A análise cardíaca incluiu: expressão das proteínas TLR-4 e NF-ĸB, níveis de TNF-α e IL-6. Comparação pelo teste t de Student não pareado ou teste de Mann-Whitney com um valor de p <0,05 como estatisticamente significativo. Resultados O grupo OB apresentou obesidade, glicose elevada, triglicerídeos, ácido úrico, HOMA, pressão arterial sistólica e TNF-α no tecido adiposo. O grupo OB apresentou remodelação cardíaca e disfunção diastólica. A expressão de TLR-4 e NF-ĸB e os níveis de citocinas foram maiores em OB. Conclusão Nossos achados concluem que, em uma condição obesogênica, a inflamação derivada da ativação do TLR-4 cardíaco pode ser um mecanismo capaz de levar à remodelação e disfunção cardíaca.

Abstract Background Obesity is a chronic low-grade inflammation condition related to cardiac disorders. However, the mechanism responsible for obesity-related cardiac inflammation is unclear. The toll-like receptor 4 (TLR-4) belongs to a receptor of the transmembrane family responsible for the immune response whose activation stimulates the production of proinflammatory cytokines. Objective To test whether the activation of the TLR-4 receptor participates in the obesity cardiomyopathy process, due to cytokine production through NF-ĸB activation. Methods Male Wistar rats were randomized into two groups: the control group (C, n= 8 animals) that received standard diet/water and the obese group (OB, n= 8 animals) that were fed a high sugar-fat diet and water plus 25% of sucrose for 30 weeks. Nutritional analysis: body weight, adiposity index, food, water, and caloric intake. Obesity-related disorders analysis: plasma glucose, uric acid and triglycerides, HOMA-IR, systolic blood pressure, TNF-α in adipose tissue. Cardiac analysis included: TLR-4 and NF-ĸB protein expression, TNF-α and IL-6 levels. Comparison by unpaired Student's t-test or Mann- Whitney test with a p-value < 0.05 as statistically significant. Results The OB group showed obesity, high glucose, triglycerides, uric acid, HOMA, systolic blood pressure, and TNF-α in adipose tissue. OB group presented cardiac remodeling and diastolic dysfunction. TLR-4 and NF-ĸB expression and cytokine levels were higher in OB. Conclusion Our findings conclude that, in an obesogenic condition, the inflammation derived from cardiac TLR-4 activation can be a mechanism able to lead to remodeling and cardiac dysfunction.