Oral Angiotensin-(1-7) prevented obesity and hepatic inflammation by inhibition of resistin/TLR4/MAPK/NF-κB in rats fed with high-fat diet.

Obesity is characterized by a pro-inflammatory state commonly associated with type 2 diabetes and fat-liver disease. In the last few years, different studies pointed out the role of Angiotensin (Ang)-(1-7) in the metabolic regulation. The aim of the present study was to evaluate the effect of oral-administration of Ang-(1-7) in metabolism and inflammatory state of high-fat feed rats. Twenty-four male Sprague Dawley rats were randomized into three groups: High Fat Diet (HFD); Standard Diet (ST); High Fat Diet+Angiotensin-(1-7) [HFD+Ang-(1-7)]. Glycemic profile was evaluated by glucose tolerance and insulin sensitivity tests, plasmatic glucose and insulin. Cholesterol, HDL and triglycerides analyses presented lipidic profile. RT-PCR evaluated mRNA expression to ACE, ACE2, resistin, TLR4, IL-6, TNF-α and NF-κB genes. The main results showed that oral Ang-(1-7) decreased body weight and abdominal fat-mass. In addition, HFD+Ang-(1-7) treated rats presented enhanced glucose tolerance, insulin-sensitivity and decreased plasma-insulin levels, as well as a significant decrease in circulating lipid levels. These alterations were accompanied by a marked decreased expression of resistin, TLR4, ACE and increased ACE2 expression in liver. Furthermore, Ang-(1-7) decreases phosphorylation of MAPK and increases NF-κB expression. These alterations diminished expression of interleukin-6 and TNF-α, ameliorate inflammatory state in liver. In summary, the present study showed that oral-treatment with Ang-(1-7) in high-fat feed rats improved metabolism down-regulating resistin/TLR4/NF-κB-pathway.

Increased circulating angiotensin-(1-7) protects white adipose tissue against development of a proinflammatory state stimulated by a high-fat diet.

INTRODUCTION: The aim of the present study was to evaluate the effect of a transgenic-induced chronic increase of Ang-(1-7) on the expression of inflammatory markers in adipose tissue and the metabolic profile in rats treated with high-fat diet. RESEARCH DESIGN AND METHODS: Transgenic rats expressing an Ang-(1-7)-producing fusion protein (TGR L-3292) and Sprague Dawley (SD) control rats 4 weeks old were treated for 8 weeks with a high-fat diet. Food intake and body weight were measured once a week. Glucose-tolerance and insulin sensitivity tests were performed one week before the sacrifice. At the end of the experiment plasma lipid concentrations were measured in TGR and SD rats. Adipose tissue were weighted and corrected by the body weight. Proinflammatory markers in adipose tissue were analyzed using Western-blotting, real time-PCR and immunohistochemistry. RESULTS: High-fat diet TGR rats presented increased HDL cholesterol levels and decreased abdominal fat mass, without changes in food intake. In addition, rats with increased Ang-(1-7) levels had lower body weight. Molecular analysis revealed decreased IL-1ß and COX-2 in adipose tissue. CONCLUSIONS: Taken together, these results show that chronic high circulating angiotensin-(1-7) levels protect against metabolic stress induced by a high-fat diet decreasing the proinflammatory profile of adipose tissue.

Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism.

OBJECTIVE: Metabolic syndrome is characterized by the variable coexistence of obesity, hyperinsulinemia, insulin resistance, dyslipidemia, and hypertension. It is well known that angiotensin (Ang) II is importantly involved in the metabolic syndrome. However, the role of the vasodilator Ang-(1-7)/Mas axis is not known. The aim of this study was to evaluate the effect of genetic deletion of the G protein-coupled receptor, Mas, in the lipidic and glycemic metabolism in FVB/N mice. RESEARCH DESIGN AND METHODS: Plasma lipid, insulin, and cytokine concentrations were measured in FVB/N Mas-deficient and wild-type mice. A glucose tolerance test was performed by intraperitoneally injecting d-glucose into overnight-fasted mice. An insulin sensitivity test was performed by intraperitoneal injection of insulin. Uptake of 2-deoxy-[(3)H]glucose by adipocytes was used to determine the rate of glucose transport; adipose tissue GLUT4 was quantified by Western blot. Gene expression of transforming growth factor (TGF)-beta, type 1 Ang II receptor, and angiotensinogen (AGT) were measured by real-time PCR. RESULTS: Despite normal body weight, Mas-knockout (Mas-KO) mice presented dyslipidemia, increased levels of insulin and leptin, and an approximately 50% increase in abdominal fat mass. In addition, Mas gene-deleted mice presented glucose intolerance and reduced insulin sensitivity as well as a decrease in insulin-stimulated glucose uptake by adipocytes and decreased GLUT4 in adipose tissue. Mas(-/-) presented increased muscle triglycerides, while liver triglyceride levels were normal. Expression of TGF-beta and AGT genes was higher in Mas-KO animals in comparison with controls. CONCLUSIONS: These results show that Mas deficiency in FVB/N mice leads to dramatic changes in glucose and lipid metabolisms, inducing a metabolic syndrome-like state.

Efeito da goma guar parcialmente hidrolisada no metabolismo de lipídeos e na aterogênese de camundongos / Effect of partially hydrolyzed guar gum on lipid metabolism and atherogenesis of mice

OBJETIVO: Observar os efeitos da goma guar parcialmente hidrolisada no metabolismo de colesterol e na formação de placa aterosclerótica em aorta de camundongos deficientes no receptor LDL, euglicêmicos ou com hiperglicemia induzida por estreptozotocina. MÉTODOS: Trinta e seis camundongos deficientes para o receptor de LDL foram divididos em quatro grupos de nove animais: grupos euglicêmicos, alimentados com dieta aterogênica padrão (controle euglicêmico) ou suplementada com 7,5 por cento de goma guar parcialmente hidrolisada (goma guar parcialmente hidrolisada euglicêmico) e grupos hiperglicêmicos alimentados com dieta aterogênica padrão (controle hiperglicêmico) ou suplementada com 7,5 por cento de goma guar parcialmente hidrolisada (goma guar parcialmente hidrolisada hiperglicêmico). Após quatro semanas de experimento foram medidos: ingestão alimentar, ganho de peso, glicemia, colesterol plasmático e hepático, assim como lesão aterosclerótica na aorta torácica e abdominal. RESULTADOS: Os resultados mostram que a suplementação de goma guar parcialmente hidrolisada levou ao aumento do colesterol hepático e plasmático em animais euglicêmicos, mas sem aumento na área de lesão aterosclerótica na aorta. Em animais hiperglicêmicos, a redução no colesterol plasmático não foi estatisticamente significante, mas no que se refere à lesão da aorta, observou-se redução significante. CONCLUSÃO: Os resultados sugerem que a goma guar parcialmente hidrolisada pode reduzir a aterosclerose associada ao Diabetes Mellitus tipo 1.

OBJECTIVE: The objective of this study was to observe the effects of partially hydrolyzed guar gum on cholesterol metabolism and atherosclerosis in the aorta of euglycemic and streptozotocin-induced hyperglycemic LDL receptor deficient mice. METHODS: Thirty six LDL receptor deficient mice were divided into 4 groups of 9 animals: euglycemic groups fed on hypercholesterolemic diet without or supplemented with 7.5 percent of partially hydrolyzed guar gum and streptozotocin-induced hyperglycemic groups also fed an atherogenic diet without or supplemented with 7.5 percent of partially hydrolyzed guar gum. After 4 weeks of experiment, food intake, body weight, glycemia, blood and liver cholesterol and atherosclerotic lesion in the aorta were determined. RESULTS: The results showed that partially hydrolyzed guar gum induced an increase in blood and liver cholesterol in euglycemic mice when compared with euglycemic control groups at the end of the experiment. On the other hand, although not affecting plasma cholesterol, hyperglycemic mice supplemented with partially hydrolyzed guar gum had the lesion area in the aorta significantly reduced. In hyperglycemic animals, plasma cholesterol did not decrease significantly but the lesion area in the aorta did. CONCLUSION: The present study suggests that partially hydrolyzed guar gum can reduce the development of atherosclerosis associated with type 1 diabetes mellitus.