angiotensin-i and Weight-Gain

Temporal lobe epilepsy (TLE) is the most frequent type of epilepsy and is often refractory to pharmacological treatment. In this scenario, extensive research has identified components of the renin-angiotensin system (RAS) as potential therapeutic targets. Therefore, the aim of the present study was to evaluate the effects of long-term treatment with angiotensin-(1-7) [Ang-(1-7)] in male Wistar rats with TLE induced by pilocarpine (PILO). Rats with TLE were submitted to intracerebroventricular (icv) infusion of Ang-(1-7) (200 ng/kg/h) for 28 days, starting at the first spontaneous motor seizure (SMS). Body weight, food intake, and SMS were evaluated daily. Behavioral tests and hippocampal protein levels were also evaluated at the end of the treatment. Ang-(1-7) treatment reduced the frequency of SMS and attenuated low anxiety levels, increased locomotion/exploration, and reduced body weight gain that was induced by TLE. Moreover, Ang-(1-7) positively regulated the hippocampal levels of antioxidant protein catalase and antiapoptotic protein B-cell lymphoma 2 (Bcl-2), as well as mammalian target of rapamycin (mTOR) phosphorylation, which were reduced by TLE. The hippocampal up-regulation of angiotensin type 1 receptor induced by TLE was also attenuated by Ang-(1-7), while the Mas receptor (MasR) was down-regulated compared with epilepsy. These data show that Ang-(1-7) presents an antiepileptic effect, increasing neuroprotection markers and reducing SMS frequency, body weight, and behavior impairments found in TLE. Therefore, Ang-(1-7) is a promising coadjutant therapeutic option for the treatment of TLE.

Topics: Angiotensin I; Animals; Anticonvulsants; Anxiety; Disease Models, Animal; Elevated Plus Maze Test; Epilepsy, Temporal Lobe; Hippocampus; Infusions, Intraventricular; Male; Motor Activity; Peptide Fragments; Photoperiod; Rats, Wistar; Weight Gain

Angiotensin-converting enzyme 2 (ACE2) has been identified in pancreatic islets and can preserve β cells. In this study, we aimed to examine the possible role of ACE2 and its end product, angiotensin 1-7 (A1-7), in reducing β cell dedifferentiation during metabolic stress.. First, a lineage-tracing experiment was performed to track β cells in mice fed a high-fat diet (HFD). Second, the ACE2/A1-7 axis was evaluated in the HFD mouse model. Intraperitoneal glucose tolerance tests (IPGTTs) and intraperitoneal insulin tolerance tests (IPITTs) were conducted. Phenotypic changes in β cells were detected by immunohistochemistry and quantitative real-time PCR. Pancreatic sections were immunostained for vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS). Finally, the effects of the ACE2/A1-7 axis were explored in isolated mouse islets exposed to different concentrations of glucose. Glucose-stimulated insulin release and levels of insulin mRNA and OCT4 mRNA were measured.. Pancreatic β cell dedifferentiation occurred both in vitro and in vivo in response to metabolic stress and was accompanied by ACE2 reduction. HFD-induced insulin resistance and glucose intolerance were exacerbated in ACE2-knockout (ACE2KO) mice but were alleviated by exogenous A1-7 in C57BL/6J mice. Approximately 20% of β cells were dedifferentiated in ACE2KO mice fed a standard rodent chow diet (SD). A higher percentage of dedifferentiated β cells was detected in ACE2KO mice than in wild-type (WT) mice under HFD conditions. In contrast, the administration of A1-7 alleviated HFD-induced β cell dedifferentiation in C57BL/6J mice. Moreover, the exogenous injection of A1-7 improved microcirculation in islets and decreased the production of iNOS in islets of C57BL/6J mice fed an HFD. Additionally, ACE2 was found to be mainly expressed in α cells of mice, while Mas, the receptor of A1-7, was distributed in β cells.. Overall, this study is the first to demonstrate that the ACE2/A1-7/Mas axis may be one of the intra-islet paracrine mechanisms of communication between α and β cells. Enhancing the ACE2/A1-7 axis exerts a protective effect by ameliorating β cell dedifferentiation, and this effect might be partially mediated through improvements in islet microcirculation and suppression of islet iNOS.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Cell Dedifferentiation; Cell Lineage; Diet, High-Fat; Glucose Intolerance; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Peptidyl-Dipeptidase A; Weight Gain

Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.

Topics: Adiponectin; Adipose Tissue; AMP-Activated Protein Kinases; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Blood Glucose; Blotting, Western; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Glucose Intolerance; Heart; Heart Failure; Humans; Inflammation; Insulin Resistance; Macrophages; Mice; Mice, Knockout; Myocardium; Obesity; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Pericardium; Phosphorylation; Real-Time Polymerase Chain Reaction; Stroke Volume; Tumor Necrosis Factor-alpha; Vasodilator Agents; Weight Gain

Angiotensin AT1 receptor antagonists induce weight loss; however, the mechanism underlying this phenomenon is unknown. The Mas receptor agonist angiotensin-(1-7) is a metabolite of angiotensin I and of angiotensin II . As an agonist of Mas receptors, angiotensin-(1-7) has beneficial cardiovascular and metabolic effects.. We investigated the anti-obesity effects of transgenically overexpressed angiotensin-(1-7) in rats. We secondly examined whether weight loss due to telmisartan (8 mg·kg(-1) ·d(-1) ) in diet-induced obese Sprague Dawley (SD) rats can be blocked when the animals were co-treated with the Mas receptor antagonist A779 (24 or 72 μg·kg(-1) ·d(-1) ).. In contrast to wild-type controls, transgenic rats overexpressing angiotensin-(1-7) had 1.) diminished body weight when they were regularly fed with chow; 2.) were protected from developing obesity although they were fed with cafeteria diet (CD); 3.) showed a reduced energy intake that was mainly related to a lower CD intake; 5.) remained responsive to leptin despite chronic CD feeding; 6.) had a higher, strain-dependent energy expenditure, and 7.) were protected from developing insulin resistance despite CD feeding. Telmisartan-induced weight loss in SD rats was partially antagonized after a high, but not a low dose of A779.. Angiotensin-(1-7) regulated food intake and body weight and contributed to the weight loss after AT1 receptor blockade. Angiotensin-(1-7)-like agonists may be drug candidates for treating obesity.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Animals, Genetically Modified; Benzimidazoles; Benzoates; Diet; Energy Intake; Energy Metabolism; Insulin Resistance; Leptin; Male; Obesity; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Receptors, G-Protein-Coupled; Signal Transduction; Telmisartan; Weight Gain; Weight Loss

Angiotensin-(1-7) has been described as a new potential therapeutic tool for the treatment and prevention of metabolic disorders by regulating several pathways in visceral white adipose tissue (vWAT). The aim of this study was to access the proteins differentially regulated by Ang-(1-7) using proteomic analysis of visceral adipose tissue. Male mice were divided into three groups and fed for 60 days, with each group receiving one of the following diets: standard diet+HPβCD (ST), high fat diet+HPβCD (HFD) and high fat diet+Ang-(1-7)/HPβCD (HFD+Ang-(1-7)). Body weight, fat weight and food intake were measured. At the end of treatment, Ang-(1-7) induced a decrease in body and fat weight. Differential proteomic analysis using two-dimensional electrophoresis (2-DE) combined with mass spectrometry were performed. Results of protein mapping of mesenteric adipose tissue using 2-DE revealed the presence of about 450 spots in each gel (n=3/treatment) with great reproducibility (>70%). Image analysis and further statistical analysis allowed the detection and identification of eight proteins whose expression was modulated in response to HFD when compared to ST. Among these, two proteins showed a sensitive response to Ang-(1-7) treatment (eno1 and aldehyde dehydrogenase). In addition, three proteins were expressed statistically different between HFD+Ang-(1-7) and HFD groups, and four proteins were modulated compared to standard diet. In conclusion, comparative proteomic analysis of a mice model of diet-induced obesity allowed us to outline possible pathways involved in the response to Ang-(1-7), suggesting that Ang-(1-7) may be a useful tool for the treatment of metabolic disorders.

Topics: Adipose Tissue, White; Administration, Oral; Angiotensin I; Animals; Diet, High-Fat; Electrophoresis, Gel, Two-Dimensional; Male; Mass Spectrometry; Mice; Mice, Inbred Strains; Obesity; Peptide Fragments; Proteome; Proteomics; Weight Gain

Obesity promotes hypertension, but it is unclear if sex differences exist in obesity-related hypertension. Angiotensin converting enzyme 2 (ACE2) converts angiotensin II (AngII) to angiotensin-(1-7) (Ang-[1-7]), controlling peptide balance. We hypothesized that tissue-specific regulation of ACE2 by high-fat (HF) feeding and sex hormones contributes to sex differences in obesity-hypertension.. HF-fed females gained more body weight and fat mass than males. HF-fed males exhibiting reduced kidney ACE2 activity had increased plasma angiotensin II levels and decreased plasma Ang-(1-7) levels. In contrast, HF-fed females exhibiting elevated adipose ACE2 activity had increased plasma Ang-(1-7) levels. HF-fed males had elevated systolic and diastolic blood pressure that were abolished by losartan. In contrast, HF-fed females did not exhibit increased systolic blood pressure until females were administered the Ang-(1-7) receptor antagonist, D-Ala-Ang-(1-7). Deficiency of ACE2 increased systolic blood pressure in HF-fed males and females, which was abolished by losartan. Ovariectomy of HF-fed female mice reduced adipose ACE2 activity and plasma Ang-(1-7) levels, and promoted obesity-hypertension. Finally, estrogen, but not other sex hormones, increased adipocyte ACE2 mRNA abundance.. These results demonstrate that tissue-specific regulation of ACE2 by diet and sex hormones contributes to sex differences in obesity-hypertension.

Topics: 3T3-L1 Cells; Adipocytes; Adiposity; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Diet, High-Fat; Disease Models, Animal; Estrogens; Female; Gene Expression Regulation, Enzymologic; Hypertension; Losartan; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Ovariectomy; Peptide Fragments; Peptidyl-Dipeptidase A; Progesterone; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Risk Factors; RNA, Messenger; Sex Factors; Testosterone; Time Factors; Weight Gain

Angiotensin-(1-7) [Ang-(1-7)] plays a beneficial role in cardiovascular physiology by providing a counterbalance to the function of angiotensin II (Ang II). Although Ang II has been shown to be an adipokine secreted by adipocyte and affect lipid metabolism, the role of Ang-(1-7) in adipose tissue remains to be clarified. The aim of the present study was to investigate whether Ang-(1-7) affects lipid metabolism in adipose tissue. Ang-(1-7) increased glycerol release from primary adipocytes in a dose-dependent manner. A lipolytic effect of Ang-(1-7) was attenuated by pretreatment with A-779, a Mas receptor blocker and with an inhibitor of phosphoinositol 3-kinase (PI3K), or eNOS. However, losartan and PD123319 did not cause any change in Ang-(1-7)-induced lipolysis. Ang-(1-7)-induced lipolysis had an addictive effect with isoproterenol. In normal rats, chronic intake of captopril for 4 wks decreased body weight gain and the amount of adipose tissue and increased plasma Ang-(1-7) level. These effects were attenuated by administration of A-779. The levels of Mas receptor and phosphorylation of hormone-sensitive lipase (p-HSL) were significantly increased by treatment with captopril and these captopril-mediated effects were attenuated by the administration of A-779. There was no difference in diameter of adipocytes among sham, captopril- and captopril+A-779-treated groups. The similar effects of captopril on body weight, expression of Mas receptor, and p-HSL were observed in Ang-(1-7)-treated rats. These results suggest that captopril intake decreased body weight gain partly through Ang-(1-7)/Mas receptor/PI3K pathway.

Topics: Adipocytes; Adipose Tissue; Adiposity; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Cell Size; Cells, Cultured; Epididymis; Glycerol; Lipolysis; Male; Peptide Fragments; Primary Cell Culture; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Sterol Esterase; Weight Gain