The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

Abstract

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions. To characterize the heart failure component of cardiometabolic syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in lean and obese ZSF1 19-to 32-week-old male rats. Histopathological assessment of kidneys and hearts was performed. Cardiac function, exercise capacity, and left ventricular gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-seq results demonstrated changes in left ventricular gene expression associated with fatty acid and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established heart failure with preserved ejection fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective effect in obese ZSF1 rats.

Anti-Inflammatory and Antioxidant Properties of Tart Cherry Consumption in the Heart of Obese Rats

“…In male C57/BL6J mice, Calligaris et al reported that feeding with an HFD for 16 months was required to develop substantial cardiac fibrosis and hypertrophy [45]. In addition, 20-week-old obese Zucker diabetic fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) male rats showed important alterations in major systemic biomarkers of cardiovascular function without histopathological modifications in the heart [46].…”

GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion

“…Furthermore, GDF15 was protective of β-cells, and administration of GDF15 prevented diabetes onset in mice ( 34 ). In addition, 12 weeks of GDF15 treatment improved exercise capacity in obese ZSF1 rats ( 35 ). Collectively, these reports indicate that skeletal muscle GDF15 may synergistically enhance β-cell function.…”

A small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase improves obesity, nephropathy and cardiomyopathy in obese ZSF1 rats

“…In aged obese ZSF1 rats with advanced renal disease, chronic treatment with 2-methoxyestradiol and its structural analog 2-ethoxyestradiol downregulated renal VEGF expression and provided renal protection [ 70 ]. Treatment with growth differentiation factor 15 decreased body weight, food intake, blood glucose, and triglycerides and improved exercise capacity in obese ZSF1 males while decreasing VEGF [ 71 ]. VEGF is a marker of vascular injury and inflammation, and as such may not be directly responsible for ZSF1 comorbidities but may help monitor disease progression and correction by therapeutic agents [ 24 ].…”