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.