Adropin reverses cardiac remodeling and metabolic dysfunction in male mouse HFpEF model by targeting LCAD O-GlcNAcylation

Heart failure with preserved ejection fraction (HFpEF) is a complex, heterogeneous cardiometabolic disease characterized by left ventricular diastolic dysfunction, myocardial stiffness, and structural remodeling. A core pathophysiological driver of HFpEF is deleterious changes in cardiac metabolism, for which current treatments often fall short in addressing the underlying defects. Adropin, an endogenous peptide hormone derived from the liver and brain, is being investigated for its role in energy homeostasis and metabolic regulation, making it a candidate for addressing the metabolic dysfunction central to HFpEF.

Researchers utilized a preclinical male mouse model designed to recapitulate cardiometabolic HFpEF to investigate molecular mechanisms and test therapeutic interventions. The study administered recombinant adropin via long-term treatment to these mice. Key endpoints included assessing markers of cardiac dysfunction such as fibrosis, diastolic function, and cardiomyocyte hypertrophy. Additionally, untargeted metabolomics was employed to analyze metabolic pathways, specifically focusing on hexosamine biosynthesis pathway activity and the O-GlcNAcylation status of the cardiac fatty acid oxidation enzyme long chain acyl-CoA dehydrogenase (LCAD).

Long-term treatment with adropin successfully reversed multiple markers of HFpEF-related cardiac dysfunction in the male mouse model. These improvements included a reduction in cardiac fibrosis, amelioration of diastolic dysfunction, and a decrease in cardiomyocyte hypertrophy. Untargeted metabolomics revealed that adropin treatment significantly reduced hexosamine biosynthesis pathway activity. This reduction directly led to a decrease in the O-GlcNAcylation of the crucial cardiac fatty acid oxidation enzyme, LCAD. Further in vitro experiments confirmed that reducing LCAD O-GlcNAcylation increased LCAD activity. In the in vivo HFpEF mouse hearts, this mechanistic improvement translated to a reduction in the accumulation of long-chain acylcarnitines, indicating restored cardiac metabolic function.

Adropin treatment significantly reduced hexosamine biosynthesis pathway activity, leading to decreased O-GlcNAcylation of the cardiac fatty acid oxidation enzyme LCAD, thereby restoring cardiac metabolic function.