Abstract 1658: The Citrus Flavonoid, Naringenin Corrects the Dyslipidemia and Improves Insulin-Sensitivity in High-Fat Fed LDLR-/- Mice
Insulin resistance is characterized by an overproduction of hepatic very low density lipoproteins (VLDL) with dyslipidemia and hyperglycemia. Our recent studies showed that naringenin, a citrus flavonoid, potently inhibits apolipoprotein B100 (apoB100) secretion from HepG2 cells and primary mouse hepatocytes by activating insulin signaling through a mechanism independent of the insulin receptor. Our current objectives were to determine if naringenin could prevent the insulin resistance, dyslipidemia and hyperglycemia observed in low density lipoprotein receptor null (LDLR-/-) mice fed a high saturated fat (Western) diet (42% calories from fat and 0.05% cholesterol). Four groups of mice (chow, Western and Western plus 1% or 3% w/w naringenin) were fed ad libitum for 4 weeks (n=12/group). Western-fed mice accrued the most body weight, and despite similar caloric intake, supplementation with 3% naringenin attenuated weight to levels similar to chow mice. Fasting plasma cholesterol (C) and triglyceride (TG) were significantly elevated in the Western- compared to chow-fed mice (21.7 vs. 6.3 and 3.8 vs. 1.0 mmol/L, respectively), which were dose-dependently decreased in the group receiving 3% naringenin (to 15.5 and 2.1 mmol/L, respectively). Naringenin attenuated the increases in VLDL-C, VLDL apoB100 and VLDL apoB48 observed in the Western-fed mice. Metabolic studies employing Triton WR-1339 showed that the increased VLDL-TG secretion in Western-fed mice was reduced by 50% with addition of 3% naringenin, suggesting that naringenin inhibits VLDL apoB secretion. Furthermore, naringenin dose-dependently reduced liver and intestinal lipids to concentrations similar to chow-fed mice. Fasting blood glucose and plasma insulin were significantly higher in the Western- compared to chow-fed mice and both variables were dose-dependently normalized by naringenin. Glucose- and insulin-tolerance tests revealed that naringenin dose-dependently corrected the impaired glucose tolerance and insulin resistance in Western-fed mice. Therefore, these in vivo studies demonstrate that naringenin ameliorates the dyslipidemia and hyperglycemia in Western-fed LDLR-/- mice and suggest novel pathways to modulate the consequences of insulin resistance.