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

Abstract

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.

• Authors: Erin E Mulvihill, Emma M Allister, Brian G Sutherland, Dawn E Telford, Cynthia G Sawyez, Jane Y Edwards, Janet M Markle, Robert A Hegele, Murray W Huff
• Journal: Diabetes (Diabetes) Vol. 58 Issue 10 Pg. 2198-210 (Oct 2009) ISSN: 1939-327X [Electronic] United States
• PMID: 19592617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Alanine Transaminase (blood)
• Animals
• Anti-Ulcer Agents (pharmacology)
• Apolipoproteins B (biosynthesis, drug effects, 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)