Geniposide Protects against Obesity‐Related Cardiac Injury through AMPKα‐ and Sirt1‐Dependent Mechanisms

Our previous study found that geniposide, an agonist of glucagon-like peptide-1 receptor (GLP-1R), protected against cardiac hypertrophy via the activation of AMP-activated protein kinase α (AMPKα). However, the effects of geniposide on obesity-related cardiac injury remain unknown. Here, we examine whether geniposide attenuates obesity-related cardiac dysfunction. Adult mice were fed a high-fat diet (HFD) for 24 weeks to induce obesity, with the last 3 weeks including a 21-day treatment with geniposide. Morphological changes, cardiac function, and remodeling were assessed. HFD-induced metabolic syndrome, featured as obesity, hyperglycemia, and cardiac hypertrophy, was prevented by geniposide treatment. Geniposide preserved cardiac function in the obese mice. Furthermore, geniposide attenuated myocardial inflammation and myocyte apoptosis induced by HFD. Geniposide activated AMPKα and sirtuin (Sirt1) in vivo and in vitro. Ampkα deficiency reversed the inhibitory effects of geniposide on cell loss. Sirt1 deficiency abolished the inhibitory effects of geniposide on inflammation in the cardiomyocytes. Geniposide completely lost its protective effects on Ampkα knockout mice after Sirt1 deficiency achieved by a nanoparticle transfection reagent. The activation of Sirt1 by geniposide was abolished by Glp-1r deficiency in vitro. Geniposide reverses molecular pathology and cardiac dysfunction via both AMPKα- and Sirt1-dependent mechanisms. Geniposide is a potential therapeutic drug for cardiovascular complications induced by obesity.