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

Diabetes. 2009 Oct;58(10):2198-210. doi: 10.2337/db09-0634. Epub 2009 Jul 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Anti-Ulcer Agents / pharmacology*
  • Apolipoproteins B / biosynthesis
  • Apolipoproteins B / drug effects
  • Apolipoproteins B / metabolism
  • Aspartate Aminotransferases / blood
  • Blood Glucose / metabolism*
  • Body Weight
  • DNA, Mitochondrial / genetics
  • Dietary Fats / pharmacology
  • Dyslipidemias / prevention & control*
  • Energy Intake
  • Estrogen Antagonists / pharmacology*
  • Flavanones / pharmacology*
  • Glucose Tolerance Test
  • Insulin / blood
  • Insulin Resistance / physiology*
  • Lipoproteins, VLDL / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, LDL / deficiency*
  • Triglycerides / metabolism


  • Anti-Ulcer Agents
  • Apolipoproteins B
  • Blood Glucose
  • DNA, Mitochondrial
  • Dietary Fats
  • Estrogen Antagonists
  • Flavanones
  • Insulin
  • Lipoproteins, VLDL
  • Receptors, LDL
  • Triglycerides
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • naringenin