ABSTRACT
Background: Angiotensin-converting enzyme 2 (ACE2) serves protective functions in metabolic, cardiovascular, renal and pulmonary diseases and is linked to COVID-19 pathology. We explored the association between soluble AC2 (sACE2) and metabolic health and proteome dynamics during a weight loss diet intervention. Methods: We analyzed 457 healthy individuals (mean age 39.8±6.6) with BMI 28-40 kg/m2 who participated in the Diet Intervention Examining the Factors Interacting with Treatment Success (DIETFITS). Biochemical markers of metabolic health and 236 proteins measured by Olink CVD II, CVD III and Inflammation arrays were available at baseline and 6 months following dietary intervention. We determined clinical and routine biochemical correlates of the diet-induced change in sACE2 (ΔsACE2) using stepwise linear regression. We then combined feature selection models and multivariable-adjusted linear regression to identify protein dynamics associated with ΔsACE2. Results: sACE2 decreased significantly on average at 6-months in the diet intervention. A stronger decline in sACE2 during the diet intervention was independently associated with female sex, lower HOMA-IR and LDL cholesterol at baseline, and a stronger decline in HOMA-IR, triglycerides, HDL-cholesterol and fat mass. In line, participants with decreasing HOMA-IR and triglycerides had significantly higher odds for a decrease in sACE2 during the diet intervention than those who did not (P≤0.0073 for both). Feature selection models linked ΔsACE2 to changes in AMBP, E-selectin, HAOX1, KIM-1, MERTK, PGF, thrombomodulin and TRAIL-R2. ΔsACE2 remained independently associated with these protein changes in multivariable-adjusted linear regression. Conclusion: Decrease in sACE2 during a weight loss diet intervention was associated with improvements in metabolic health, fat mass and markers of angiotensin peptide metabolism, vascular injury, renal function, chronic inflammation and oxidative stress. Our findings may improve the risk stratification, prevention, and management of cardiometabolic and COVID-19- related complications. (Figure Presented).