ACE2 activator diminazene aceturate reduces adiposity but preserves lean mass in young and old rats

Abstract

The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2]/angiotensin-(1-7)[Ang-(1-7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23 months, respectively) male Fisher 344 × Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15 mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD-NMR assessments revealed that the weight-loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang-(1-7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved.

ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

“…All other mice received equivalent volumes of vehicle (saline) injections. This dose was based on several previous studies showing that the optimal dose of DIZE in inducing ACE2 activity was 15 mg/kg/ day [39,43,44] and a preliminary study of our own across a range of DIZE concentrations by IP that confirmed previous findings (data not shown).…”

Effects of Resveratrol on the Renin-Angiotensin System in the Aging Kidney

“…Second, endothelial dysfunction with aging was augmented in the ACE2-deficient mice [ 32 ]. Third, administration of an Ang 1-7 analogue was associated with improved aging-related neuroinflammation [ 33 ].…”

ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19

“…Diminazene aceturate (DIZE) is a potent ACE2 activator and has been shown to exert beneficial effects in experimental models of cardiovascular diseases [142]. Bruce et al reported that DIZE reduced adiposity but preserved lean mass with increased serum ACE2 activity in young and old rats [143]. Accumulating evidence suggests that exercise is a promising non-pharmacological intervention to modulate the RAS [144,145].…”