Adiporon Ameliorates the Progression of Heart Failure with Preserved Ejection Fraction (HFpEF) by Reducing Lipid Accumulation and Fibrosis

Research Background

Heart failure with preserved ejection fraction (HFpEF) is the most common type of heart failure, often coexisting with metabolic disorders such as obesity, diabetes, and hypertension. Although the ejection fraction in HFpEF patients is normal, diastolic dysfunction leads to ineffective ventricular filling and subsequent symptoms. Despite recent advancements in heart failure treatment, managing HFpEF remains a significant unmet need in cardiovascular medicine. Current drugs, such as angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers, while effective for heart failure with reduced ejection fraction (HFrEF), show limited improvement in HFpEF patient outcomes.

The pathogenesis of HFpEF is complex, involving multiple factors such as metabolic disorders, obesity, and abnormal lipid metabolism. Studies have shown that excessive lipid accumulation in cardiomyocytes may lead to lipotoxicity, thereby causing diastolic dysfunction. Thus, modulating lipid metabolism could become a novel strategy for treating HFpEF. Adiponectin, secreted by adipocytes, plays a significant role in metabolic syndrome, offering anti-inflammatory and anti-fibrotic effects. However, adiponectin’s complex three-dimensional structure requires injection for administration, and its overexpression may induce side effects such as left ventricular hypertrophy. Adiporon, an orally active adiponectin receptor agonist, regulates fatty acid metabolism while avoiding the adverse effects of adiponectin overexpression, making it a potential candidate for clinical application.

Research Team and Publication Information

This study was conducted by researchers including Wuping Tan, Yijun Wang, Siyi Cheng, and others from Renmin Hospital of Wuhan University, the Institute of Molecular Medicine at Wuhan University, the Hubei Key Laboratory of Autonomic Nervous System Modulation, the Taikang Center for Life and Medical Sciences at Wuhan University, the Cardiac Autonomic Nervous System Research Center of Wuhan University, the Hubei Key Laboratory of Cardiology, and the Cardiovascular Research Institute at Wuhan University. The research was published in 2025 in the Journal of Advanced Research.

Research Process and Experimental Design

1. Establishment and Treatment of HFpEF Mouse Model

The study induced an HFpEF model in mice using a high-fat diet (60%) combined with L-NAME in drinking water. The mice were then divided into two groups, receiving either Adiporon (50 mg/kg) or saline via gavage for four weeks.

2. Cardiac Function Assessment and Metabolic Analysis

Cardiac function was evaluated using echocardiography, and postmortem analyses included RNA sequencing, untargeted metabolomics, transmission electron microscopy, and molecular biology methods.

3. Data Collection and Analysis

The study collected data on cardiac function, metabolites, lipid accumulation, and fibrosis, and analyzed the data using various statistical methods.

Key Findings

1. Adiporon Upregulates Adiponectin Receptors and Reduces Lipid Accumulation

The study found that the expression of adiponectin receptors (AdipoR1/2) was downregulated, and fatty acid oxidation (FAO) was impaired in the myocardium of HFpEF mice, leading to increased lipid accumulation. Adiporon upregulated the expression of AdipoR1/2, reduced lipid droplet accumulation in cardiomyocytes, and improved cardiac function by activating AMPKα and PPARα signaling pathways.

2. Adiporon Alleviates Myocardial Fibrosis

HFpEF mice exhibited significant myocardial fibrosis, while Adiporon significantly reduced the expression of collagen I and III by regulating the AdipoR1/AMPKα/TGF-β pathway, thereby mitigating fibrosis.

3. Adiporon Improves HFpEF Phenotype by Modulating Lipid Metabolism

Adiporon restored the balance of fatty acid uptake, transport, and oxidation in the myocardium, significantly improving diastolic function, exercise tolerance, and glucose tolerance in HFpEF mice.

Research Conclusions

Adiporon ameliorates the HFpEF phenotype by upregulating adiponectin receptors and activating the AMPKα and PPARα signaling pathways, thereby reducing myocardial lipid accumulation and fibrosis. The findings highlight the potential therapeutic value of Adiporon in HFpEF.

Research Highlights

• First Discovery of Downregulated Adiponectin Receptors in HFpEF Mice: Establishes a link between HFpEF and abnormalities in lipid metabolism.
• Adiporon Improves HFpEF Phenotype by Modulating Lipid Metabolism and Fibrosis: Provides new therapeutic insights.
• Significant Protective Effects of Adiporon Under Continuous Mechanical and Metabolic Stress: Offers strong support for its clinical application.

Research Significance

This study provides a new direction for the treatment of HFpEF. Adiporon, as an orally active adiponectin receptor agonist, demonstrates significant clinical translational potential. Future research will continue to explore its mechanisms in different HFpEF models and further validate its efficacy in clinical patients.