Naringenin Prevents Dyslipidemia, Apolipoprotein B Overproduction, and Hyperinsulinemia in LDL Receptor–Null Mice With Diet-Induced Insulin Resistance

  1. Erin E. Mulvihill1,2,
  2. Emma M. Allister1,
  3. Brian G. Sutherland1,
  4. Dawn E. Telford1,3,
  5. Cynthia G. Sawyez1,3,
  6. Jane Y. Edwards1,3,
  7. Janet M. Markle1,
  8. Robert A. Hegele1,2,3,4 and
  9. Murray W. Huff1,2,3
  1. 1Department of Vascular Biology, Robarts Research Institute, London, Ontario, Canada;
  2. 2Department of Biochemistry, University of Western Ontario, London, Ontario, Canada;
  3. 3Department of Medicine, University of Western Ontario, London, Ontario, Canada;
  4. 4Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, Ontario, Canada.
  1. Corresponding author: Murray W. Huff, mhuff{at}
  1. E.E.M. and E.M.A. contributed equally to this article and are co–first authors.


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) γ coactivator 1α/PPARα-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.


  • E.M.A. is currently affiliated with the Endocrinology and Diabetes Research Group, Department of Physiology, University of Toronto, Toronto, Canada. J.M.M. is currently affiliated with the Department of Immunology, The Hospital for Sick Children, Toronto Medical Discovery Tower, Toronto, Canada.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received April 29, 2009.
    • Accepted June 22, 2009.
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