Avaliação da resposta imuno-metabólica em macrófagos peritoneais de camundongos obesos: papel do exercício físico e do PPAR-γ
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Data
2018-12-11
Autores
Silveira, Loreana Sanches
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O treinamento físico aeróbio é considerado uma terapia para doenças inflamatórias crônicas de baixo grau devido sua resposta anti-inflamatória mediada por células do sistema imunológico. O receptor ativado por proliferador de peroxissomo gama (PPAR-γ) é capaz de regular a polarização M1 (caráter pró-inflamatório) e M2 (caráter anti-inflamatório), assim como a resposta imunometabólica dos macrófagos. Desta maneira, propusermos na presente tese verificar se a deleção condicional do PPAR-γ em macrófagos teria algum efeito sobre o papel anti-inflamatório do exercício aeróbio moderado. Para testar nossa hipótese, foram utilizadas duas linhagens de animais: PPAR-γ LyzCre+/+ (KO) e animais controle da mesma ninhada (WT). Cada genótipo foi dividido em 1) dieta controle sedentário; 2) dieta controle e treinamento moderado; 3) dieta hiperlipídica sedentário (HF) e 4) dieta hiperlipídica e treinamento moderado (HFT). O protocolo experimental teve duração de doze semanas, sendo quatro semanas apenas de dieta e oito semanas de dieta e exercício. Foram avaliados o perfil metabólico dos animais e o perfil inflamatório de macrófagos peritoneais e do tecido adiposo subcutâneo (TAS). A deleção do PPAR-y não afetou a composição corporal ou o desempenho no teste físico em animais alimentados com dieta controle, no entanto o treinamento não apenas proporcionou melhoras metabólicas mas também na resposta imune de animais nocaute. A indução da obesidade promoveu hipertrofia no TAS de animais KO, no entanto o perfil inflamatório não foi exacerbado. Macrófagos peritoneais de animais KO exibiram acentuado ambiente inflamatório após estimulo com LPS. A adoção do programa de treinamento físico aeróbio moderado protegeu ambos os genótipos do ganho de peso, reduziu a ingestão calórica e a hipertrofia do TAS de animais KO. O treinamento físico modulou a produção de citocinas em macrófagos peritoneais, embora a polarização M2 tenha exibido atenuação na ausência de PPAR-γ. Tomados em conjunto, nossos achados demonstram importante papel modulador do fator de transcrição PPAR-γ em marcadores M2 de macrófagos, porém sua deleção não impediu os efeitos anti-inflamatórios mediados pelo exercício físico.
Aerobic physical training is considered a therapy for chronic low-grade inflammatory diseases due to its anti-inflammatory response mediated by immune cells. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is able to regulate the M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization, as well as the immunometabolic response of macrophages. Thus, we propose in the present thesis to verify whether the conditional deletion of PPAR-γ in macrophages would have any effect on the anti-inflammatory role of moderate aerobic exercise. To test our hypothesis, two animal strains were used: PPAR-γ LyzCre+/+ (KO) and littermates control animals (WT). Each genotype was divided into 1) sedentary control diet; 2) control diet and moderate training (T); 3) sedentary high fat diet (HF) and 4) high fat diet and moderate training (HFT). The experimental protocol lasted for 12 weeks, four weeks of diet only and eight weeks of diet and exercise. The metabolic profile of the animals and the inflammatory profile of peritoneal macrophages and subcutaneous adipose tissue (SAT) were evaluated. The PPAR-γ deletion did not affect body composition or physical test performance in control diet fed animals, however the training not only provided metabolic but also the immune response enhancements on knockout animals. The induction of obesity promoted hypertrophy in the SAT, though the inflammatory profile was not exacerbated in KO animals. Peritoneal macrophages of KO animals exhibited a marked inflammatory environment after LPS stimulation. The moderate aerobic training program protected both genotypes from weight gain, reduced caloric intake and hypertrophy of SAT from KO animals. Training modulated cytokine production in peritoneal macrophages, although M2 polarization exhibited attenuation in the absence of PPAR-γ. In summary, our findings demonstrate an important modulatory role of the transcription factor PPAR-γ in macrophages M2 markers, but its deletion did not prevent the exercise-mediated anti-inflammatory effect.
Aerobic physical training is considered a therapy for chronic low-grade inflammatory diseases due to its anti-inflammatory response mediated by immune cells. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is able to regulate the M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization, as well as the immunometabolic response of macrophages. Thus, we propose in the present thesis to verify whether the conditional deletion of PPAR-γ in macrophages would have any effect on the anti-inflammatory role of moderate aerobic exercise. To test our hypothesis, two animal strains were used: PPAR-γ LyzCre+/+ (KO) and littermates control animals (WT). Each genotype was divided into 1) sedentary control diet; 2) control diet and moderate training (T); 3) sedentary high fat diet (HF) and 4) high fat diet and moderate training (HFT). The experimental protocol lasted for 12 weeks, four weeks of diet only and eight weeks of diet and exercise. The metabolic profile of the animals and the inflammatory profile of peritoneal macrophages and subcutaneous adipose tissue (SAT) were evaluated. The PPAR-γ deletion did not affect body composition or physical test performance in control diet fed animals, however the training not only provided metabolic but also the immune response enhancements on knockout animals. The induction of obesity promoted hypertrophy in the SAT, though the inflammatory profile was not exacerbated in KO animals. Peritoneal macrophages of KO animals exhibited a marked inflammatory environment after LPS stimulation. The moderate aerobic training program protected both genotypes from weight gain, reduced caloric intake and hypertrophy of SAT from KO animals. Training modulated cytokine production in peritoneal macrophages, although M2 polarization exhibited attenuation in the absence of PPAR-γ. In summary, our findings demonstrate an important modulatory role of the transcription factor PPAR-γ in macrophages M2 markers, but its deletion did not prevent the exercise-mediated anti-inflammatory effect.
Descrição
Palavras-chave
Exercício físico moderado, Sistema imunológico, Metabolismo, Citocinas, Fatores transcricionais, Moderate physical exercise, Immune system, Metabolism, Cytokines, Transcriptional factors