Uncovering the role of prokineticin pathway on Epicardial Adipose Tissue (EAT) development and EAT-associated cardiomyopathy.

Abstract

Epicardial adipose tissue (EAT), a unique fat depot surrounding the heart, plays a multifaceted role in glucose and lipid metabolism, thermogenesis, and the secretion of bioactive molecules that influence cardiac structure and function. Its proximity to the myocardium allows it to contribute directly to CVDs, including coronary artery disease, arrhythmias, and heart failure. In particular, excessive EAT has emerged as a significant factor in heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure, especially in individuals with obesity and diabetes. Traditional metrics like body mass index (BMI) fail to capture the complexities of visceral fat, as patients with similar BMIs can exhibit varying CVD risks. EAT accumulation induces mechanical stress and fosters a pro-inflammatory and fibrotic environment, driving cardiac remodeling and dysfunction. Pharmacological modulation of EAT has shown promise in delivering cardiometabolic benefits. Recent advancements in diabetes therapies, such as SGLT2 inhibitors and GLP-1 receptor agonists, and antilipidemic drugs have demonstrated their potential in reducing pro-inflammatory cytokine production and improving glucose regulation, which directly influences EAT. These discoveries suggest that EAT could be a significant therapeutic target, though further investigation is necessary to elucidate its role in HFpEF and other CVDs. Recent advances have identified the prokineticin/PKR1 signaling pathway as pivotal in EAT development and remodeling. This pathway regulates epicardial progenitor cells (EPDCs), promoting angiogenesis while reducing EAT accumulation and metabolic stress on the heart, particularly under high-calorie conditions. Prokineticin, acting through its receptor PKR1, limits visceral adipose tissue growth, enhances insulin sensitivity, and offers cardioprotection by reducing oxidative stress and activating cellular survival pathways. In this review, we provide a comprehensive analysis of EAT's role in CVDs, explore novel therapeutic strategies targeting EAT, and highlight the potential of prokineticin signaling as a promising treatment for HFpEF, obesity, and diabetes.