Dietary grape seed extract inhibits glucose intolerance and loss of metabolic flexibility induced by high‐fat diet

Abstract

Previous studies have shown that grape seed extract (GSE) inhibits diet‐induced obesity and biomarkers of type 2 diabetes. However, the exact mechanism of action is unknown. The objective of this study was to determine if reduced metabolic endotoxemia and improved metabolic flexibility are associated with reduced obesity and improved glucose tolerance due to GSE administration during high‐fat feeding. Male C57BL/6J mice (JAX, Bar Harbor, ME) were fed control (10% kcal fat) and high fat diets (45% kcal fat) containing GSE doses of 0, 10, 50, 100 mg/kg body weight (n=8/treatment) for 16 weeks. High fat feeding caused significant increases in weight gain, body fat %, and fat mass gain compared to control diet, and these increases were not significantly inhibited by GSE. High fat feeding significantly increased 12 h fasting blood glucose and 4 h oral glucose tolerance 160±11 mg/dL, 550160±11 35 mg*h/dL) compared to control (116±3.2 mg/dL, 391160±15 mg*h/dL), and GSE significantly inhibited these increases in (120±13 mg/dL, 439160±1128 mg*h/dL). GSE was not effective at improving insulin resistance induced by high‐fat feeding. Following sacrifice, skeletal muscle metabolism and metabolic flexibility were evaluated. No differences were observed in the ability of skeletal muscle to metabolize palmitic acid or glucose substrates. High fat feeding did significantly decrease substrate metabolic flexibility (as measured by both acid soluble metabolites and total metabolites), and GSE partially restored lost metabolic flexibility. These data suggest that altered metabolic flexibility (substrate switching) may be a mechanism by which GSE modulates glucose intolerance induced by high‐fat feeding.