Tributyltin impacts in metabolic syndrome development through disruption of angiotensin II receptor signaling pathways in white adipose tissue from adult female rats.

White adipose tissue (WAT) dysfunction and obesity are a consequence of a low-grade inflammation state. These WAT irregularities could result from abnormal metabolic renin-angiotensin system (RAS) control. Recently, tributyltin (TBT) has been found to play a critical role in these metabolic irregularities. However, TBT actions on the WAT-RAS functions are not currently well understood. In this study, we assessed whether TBT exposure resulted in metabolic syndrome (MetS) development and other metabolic complications as a result of abnormal modulation of WAT-RAS pathways. TBT (100 ng/kg/day) was administered to adult female Wistar rats, and their WAT morphophysiology and adipokine profiles were assessed. We further assessed the expression of Angiotensin-II receptor proteins (AT1R and AT2R) and proteins involved in downstream pathways mediating inflammation and adipogenesis modulation. TBT-exposed rats exhibited increases in body weight and adiposity. TBT rats present dyslipidemia and insulin resistance, suggesting MetS development. TBT promoted WAT inflammatory infiltration, AT1R protein overexpression and reduced Angiotensin-(1-7) expression. These TBT WAT abnormalities are reflected by NFκB activation, with higher adipokine levels (leptin, TNF-α and IL-6) and overexpression of AKT, ERK, P38, FAS and PPARγ protein. In vitro, TBT exposure stimulates lipid accumulation, reduces AT2R protein expression, and increases leptin, AKT and ERK protein expression in 3T3L1 cells. These findings suggest that TBT exposure participates in MetS development via the improper function of WAT-RAS metabolic control.

Effects of Resveratrol and ACE Inhibitor Enalapril on Glucose and Lipid Profiles in Mice.

BACKGROUND: Lipogenesis is a process that involves the fatty acids synthesis. Resveratrol and enalapril have been studied for their beneficial physiological properties on the glucose and lipid metabolism. OBJECTIVES: The aim of the present study was to evaluate the oral administration of resveratrol and enalapril effects on glucose and lipid metabolism, evaluating the white pad lipogenesis genes expression in mice. METHODS: Swiss male mice were divided into four groups and treated for eight weeks as follows: Standard diet ad libitum (G1); Standard diet + Resveratrol (G2); Standard diet + Enalapril (G3); Standard diet + Resveratrol + Enalapril (G4), where resveratrol was administered with the food and enalapril with the water. Body weight, lipid profile, adiposity, glycemic parameters and epididymal adipocytes area were assessed. The expression levels of FAS, ACC, PPARγ and SREBP-1c were assessed by RT-PCR. RESULTS: The main findings showed an improvement in the insulin sensitivity and glucose tolerance in the group G2 as compared to G1. Similar results were found for the fasting glucose levels. Decreased triglycerides were observed in the animals treated with resveratrol and enalapril, along with decreased weight of the epididymal adipose tissue in the animals of the G2 group. A mild reduction in the group G4 as compared to the group G1 was observed. Decreased mRNA expression of FAS, ACC and PPARγ in the G4 group when compared to the G1 group were observed. CONCLUSION: In conclusion the resveratrol and enalapril association improved the glucose and lipid profiles by modulating the expression of some lipogenesis genes, which are critical regulators of metabolic homeostasis.

Effects of omentectomy in addition to sleeve gastrectomy on the metabolic and inflammatory profiles of obese rats.

BACKGROUND: Visceral obesity has been considered a risk factor for metabolic and cardiovascular complications. In an attempt to reduce the visceral adipose tissue, omentectomy has been proposed to be performed along with bariatric surgery. OBJECTIVE: The goal of this study was to evaluate whether omentectomy associated with sleeve gastrectomy (SG) is beneficial to the inflammatory and metabolic profile of rats fed a standard diet (STD) or high-fat diet (HFD). SETTING: University hospital, Brazil. METHODS: For this experiment, male Wistar rats were randomly divided into 6 groups as follows: sham surgery (STD+L or HFD+L), SG alone (STD+SG or HFD+SG), or SG with omentectomy (STD+SGO or HFD+SGO). Anthropometric data and metabolic profiles were evaluated, and the tissue expression of inflammatory markers in the visceral adipose tissue was measured. RESULTS: In rats with diet-induced obesity treated with SG with or without omentectomy, there was a reduction in weight (HFD+SG: P<.01 and HFD+SGO: P<.05), adiposity (HFD+SG: P<.001 and HFD+SGO: P<.05), plasma levels of glucose (HFD+SG: P<.01 and HFD+SGO: P<.01), plasma levels of C-peptide (HFD+SG: P<.01 and HFD+SGO: P<.001), plasma levels of insulin (HFD+SG: P<.05 and HFD+SGO: P<.001), plasma levels of total cholesterol (HFD+SG: P<.01 and HFD+SGO: P<.01), and tissue expression of TNF-α (HFD+SG: P<.001 and HFD+SGO: P<.01), but there was no statistically significant difference between the groups in which omentectomy was performed or was not. CONCLUSION: In this study, we did not observe additional beneficial effects due to omentectomy associated with SG in the metabolic profile and tissue expression of inflammatory markers.

Angiotensin converting enzyme 2 activator (DIZE) modulates metabolic profiles in mice, decreasing lipogenesis.

Recent studies have shown that angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang) -(1-7)/Mas axis activation is able to improve the metabolic profile, enhance glucose tolerance and insulin sensitivity, improve metabolic parameters, and counteract deleterious effects of Ang II. The effects of endogenous ACE 2 activation on the metabolic profile of mice are poorly studied. In this study, 12 weeks old male mice were treated with the ACE 2 activator (diminazene aceturate, DIZE, 1 mg/kg/day, gavage) or saline (control) for 30 days followed by glucose tolerance tests, insulin sensitivity tests, and blood analysis. Epididymal ACE2, ACE, angiotensinogen, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) were measured by quantitative RT-PCR. ACE 2 activation treatment lowered body weight (DIZE vs control) (28.69 vs 30.28g, P < 0.001), serum cholesterol (140,0 vs 177.5; P < .05), and serum triglycerides (75,00 vs 165,0; P < .05) as well as epididymal (0.008 vs 0.016; P < .05) and retroperitoneal (0.0024 vs. 0.0068; P < .01) adipose tissue weights. These effects were associated with significantly increased epididymal ACE 2 and decreased ACE and angiotensinogen (AGT) expression. Additionally, DIZE decreased adipogenesis-related gene transcription, such as ACC and FAS mRNA. In conclusion, these results indicate that activation of ACE2 by oral DIZE treatment improves the metabolic profile and reduces fat deposition in mice. These results, along with the reduction of lipogenesis markers open a new perspective for metabolic disorder pharmacotherapy.

The role of renin-angiotensin system modulation on treatment and prevention of liver diseases.

The renin-angiotensin system (RAS) is now recognized as an important modulator of body metabolic processes. The discovery of angiotensin-converting enzyme 2 (ACE2) has renewed interest in the potential therapeutic role of RAS modulation. Recent studies have pointed out the importance of the local balance between ACE/Ang-II/AT1 and ACE2/Ang-(1-7)/Mas arms to avoid liver metabolic diseases. Furthermore, non-alcoholic fatty liver disease is an increasing health problem that includes a spectrum of hepatic steatosis, steatohepatitis and fibrosis. Some new studies revealed that RAS imbalance appears to promote hepatic fibrogenesis; while the activation of ACE2/Ang-(1-7)/Mas counter-regulatory axis is able to prevent liver injuries. In this context, the aim of the present review is to discuss the importance of RAS in the development and prevention of liver disease. AT1 receptor activation by Ang II induces hepatic stellate cell contraction and proliferation, causes oxidative stress, endothelial dysfunction, cell growth and inflammation. In addition, both AT1 blocker administration and ACE inhibitors lead to a reduction in inflammation and improvement of hepatic fibrosis. Conversely, Ang-(1-7) infusion reduces fibrosis and proliferation mainly by suppression of hepatic stellate cell activation; Mas receptor antagonism aggravates liver fibrosis and severe liver steatosis. In conclusion, the use of ACE/Ang II/AT1 axis inhibitors associated with ACE2/Ang(1-7)/Mas axis activation is a promising new strategy serving as a novel therapeutic regimen to prevent and treat chronic liver diseases as well as acute liver injury.

Diet composition modulates expression of sirtuins and renin-angiotensin system components in adipose tissue.

OBJECTIVE: The aim of this study was to evaluate the expression of RAS components and SIRTs enzymes in the adipose tissue of mice fed diets with different macronutrient composition. DESIGN AND METHODS: The body weight, food intake, and energy intake (kcal) were evaluated. Blood parameters (insulin sensitivity, glucose tolerance, total cholesterol, HDL-C triglyceride, and glucose levels) were also assessed. Real-time PCR was performed in epididymal adipose tissue samples to analyze the expression of renin, angiotensinogen (AGT), angiotensin-converting enzyme 1 and 2 (ACE and ACE2), and SIRTs 1-7. Male FVB/N mice were divided into 5 groups (N = 10 each) that were fed with experimental diets for 60 days. Test diets were divided into standard (ST), AIN-93M, high glucose (HG), high protein (HP) and high lipid (HL). RESULTS: The main results showed that HL diet treatment induced reduction in HDL-C and triglyceride plasma levels; increased ACE (Ang II marker) expression and decreased ACE2 (Ang-[1-7] catalyzer) expression in adipose tissue; and also increased SIRT4 expression. CONCLUSION: Diets with high lipid content induced a degenerative state associated with deregulation of adipose tissue enzymes expression.