Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance

Objective: The global epidemic of metabolic syndrome and its complications demands rapid evaluation of new and accessible interventions. Insulin resistance is the central biochemical disturbance in the metabolic syndrome. The citrus-derived flavonoid, naringenin, has lipid-lowering properties and inhibits VLDL secretion from cultured hepatocytes in a manner resembling Insulin. We evaluated whether naringenin regulates lipoprotein production and Insulin sensitivity in the context of Insulin resistance in vivo.

Research design and methods: LDL receptor-null (LDLR(-/-)) mice fed a high-fat (Western) diet (42% calories from fat and 0.05% Cholesterol) become dyslipidemic, Insulin and glucose intolerant, and obese. Four groups of mice (standard diet, Western, and Western plus 1% or 3% wt/wt naringenin) were fed ad libitum for 4 weeks. VLDL production and parameters of Insulin and glucose tolerance were determined.

Results: We report that naringenin treatment of LDLR(-/-) mice fed a Western diet corrected VLDL overproduction, ameliorated hepatic steatosis, and attenuated dyslipidemia without affecting caloric intake or fat absorption. Naringenin 1) increased hepatic fatty acid oxidation through a Peroxisome Proliferator-activated Receptor (PPAR) gamma coactivator 1alpha/PPARalpha-mediated transcription program; 2) prevented sterol regulatory element-binding protein 1c-mediated lipogenesis in both liver and muscle by reducing fasting hyperinsulinemia; 3) decreased hepatic Cholesterol and Cholesterol ester synthesis; 4) reduced both VLDL-derived and endogenously synthesized fatty acids, preventing muscle triglyceride accumulation; and 5) improved overall Insulin sensitivity and glucose tolerance.

Conclusions: Thus, naringenin, through its correction of many of the metabolic disturbances linked to Insulin resistance, represents a promising therapeutic approach for metabolic syndrome.