Patel, Vaibhav B.Mori, JunMcLean, Brent A.Basu, RatnadeepDas, Subhash K.Ramprasath, TharmarajanParajuli, NirmalPenninger, Josef M.Grant, Maria B.Lopaschuk, Gary D.Oudit, Gavin Y.2017-05-032017-05-032016-01Patel, V. B., Mori, J., McLean, B. A., Basu, R., Das, S. K., Ramprasath, T., … Oudit, G. Y. (2016). ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity. Diabetes, 65(1), 85–95. http://doi.org/10.2337/db15-0399https://hdl.handle.net/1805/12458Obesity 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.en-USPublisher PolicyObesityWomenAngiotensin (Ang)-converting enzyme 2Cardiac dysfunctionEpicardial adipose tissueHeart failureArticle