Abstract

Objective: The global epidemic of metabolic syndrome and its complications demand 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 very low density lipoprotein (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 Methods and Design: Low density lipoprotein 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 (chow, western and western plus 1% or 3%, w/w naringenin) were fed ad libitum for 4 weeks. Very low density lipoprotein (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 PPARγ coactivator 1 alpha, (PGC1α)/PPARα-mediated transcription program; 2) prevented SREBP1c-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 acid preventing muscle triglyceride accumulation; 5) improved overall insulin sensitivity and glucose tolerance.

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