Intervention with citrus flavonoids reverses obesity and improves metabolic syndrome and atherosclerosis in obese Ldlr-/- mice

J Lipid Res. 2018 Sep;59(9):1714-1728. doi: 10.1194/jlr.M087387. Epub 2018 Jul 15.


Obesity and its associated metabolic dysfunction and cardiovascular disease risk represent a leading cause of adult morbidity worldwide. Currently available pharmacological therapies for obesity have had limited success in reversing existing obesity and metabolic dysregulation. Previous prevention studies demonstrated that the citrus flavonoids, naringenin and nobiletin, protect against obesity and metabolic dysfunction in Ldlr-/- mice fed a high-fat cholesterol-containing (HFHC) diet. However, their effects in an intervention model are unknown. In this report, we show that, in Ldlr-/- mice with diet-induced obesity, citrus flavonoid supplementation to a HFHC diet reversed existing obesity and adipocyte size and number through enhanced energy expenditure and increased hepatic fatty acid oxidation. Caloric intake was unaffected and no evidence of white adipose tissue browning was observed. Reversal of adiposity was accompanied by improvements in hyperlipidemia, insulin sensitivity, hepatic steatosis, and a modest reduction in blood monocytes. Together, this resulted in atherosclerotic lesions that were unchanged in size, but characterized by reduced macrophage content, consistent with a more stable plaque phenotype. These studies further suggest potential therapeutic utility of citrus flavonoids, especially in the context of existing obesity, metabolic dysfunction, and cardiovascular disease.

Keywords: beta oxidation; hypolipidemic drugs; insulin resistance; low density lipoprotein receptor-deficient mice; steatohepatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / pathology
  • Animals
  • Atherosclerosis / complications*
  • Body Weight / drug effects
  • Cholesterol / metabolism
  • Citrus / chemistry*
  • Diet, High-Fat / adverse effects
  • Energy Metabolism / drug effects
  • Flavonoids / pharmacology*
  • Flavonoids / therapeutic use
  • Hyperlipidemias / complications
  • Insulin Resistance
  • Macrophages / drug effects
  • Male
  • Metabolic Syndrome / complications*
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / drug effects
  • Obesity / complications*
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Obesity / pathology
  • Receptors, LDL / deficiency*


  • Flavonoids
  • Receptors, LDL
  • Cholesterol