Dietary Eriodictyol Alleviates Adiposity, Hepatic Steatosis, Insulin Resistance, and Inflammation in Diet-Induced Obese Mice

Abstract

The present study aimed to investigate the molecular mechanisms underlying the anti-obesity effect of flavonoid eriodictyol (ED) supplementation in mice fed with a high-fat diet (HFD). C57BL/6N mice were fed with normal diet (ND), HFD (40 kcal% fat), or HFD + 0.005% (w/w) ED for 16 weeks. In HFD-induced obese mice, dietary ED supplementation significantly alleviated dyslipidemia and adiposity by downregulating the expression of lipogenesis-related genes in white adipose tissue (WAT), while enhancing fecal lipid excretion. ED additionally improved hepatic steatosis and decreased the production of pro-inflammatory cytokines by downregulating the expression of hepatic enzymes and the genes involved in lipogenesis and upregulating the expression of hepatic fatty acid oxidation-related enzymes and genes. In addition, ED improved insulin resistance (IR) by suppressing hepatic gluconeogenesis, enhancing glucose utilization, and modulating the production and release of two incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Taken together, the current findings indicated that ED can protect against diet-induced obesity and related metabolic disturbances, including dyslipidemia, inflammation, fatty liver disease, and IR in diet-induced obese mice.

Keywords: adiposity; eriodictyol; hepatic steatosis; inflammation; insulin resistance; obesity.

Figure 1

Effect of eriodictyol treatment on body weight (BW) (A), food intake (B), food efficiency ratio (C), white adipose tissue (WAT) weights (D), WAT morphology (200× magnification) and adipocyte cell size (E), and expression of adipocyte genes (F) in C57BL/6N mice fed with the high-fat diet (HFD). Data are presented as means ± SEM. Normal diet (ND; AIN-76) vs. HFD; ^* p < 0.05, ^** p < 0.01, ^*** p < 0.001. HFD vs. ED (HFD + 0.005% ED); ^§ p < 0.05, ^§§ p < 0.01, ^§§§ p < 0.001. Cd36, cd antigen 36; LPL, lipoprotein lipoase; SREBP1, sterol regulatory element-binding transcription factor 1; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; SCD1, steroly-CoA desaturase 1; ADRB3, adrenoreceptor β3; CPT2, carnitine palmitoyltransferase 2; PGC1, peroxisome proliperator-acivated receptor γ coactivator 1; COX8β, cytochrome c oxidase subunit 8β; UCP1, uncoupling protein 1.

Figure 2

Effect of eriodictyol treatment on the plasma lipid levels in C57BL/6N mice fed with the high-fat diet (HFD). Data are presented as means ± SEM. Normal diet (ND; AIN-76) vs. HFD; ^* p < 0.05, ^** p <0.01, ^*** p < 0.001. HFD vs. ED (HFD + 0.005% ED); ^§ p < 0.05, ^§§§ p < 0.001. Total-C, total-cholesterol; HDL-C, high-density lipoprotein-cholesterol; TG, triglyceride; FFA, free fatty acid; HTR, HDL-cholesterol-to-TC ratio; AI, atherogenic index; Apo, apolipoprotein.

Figure 3

Effect of eriodictyol treatment on hepatic lipid levels (A), fecal lipid levels (B), hepatic morphology (200× magnification) (C), activities of hepatic lipid-regulating enzymes (D), and expression of hepatic genes (E) in C57BL/6N mice fed with the high-fat diet (HFD). Data are presented as means ± SEM. Normal diet (ND; AIN-76) vs. HFD; ^* p < 0.05, ^** p <0.01, ^*** p < 0.001. HFD vs. ED (HFD + 0.005% ED); ^§ p < 0.05, ^§§ p < 0.01, ^§§§ p < 0.001. ME, malic enzyme; G6PD, glucose-6-phosphate dehydrogenase; FAS, fatty acid synthase; PAP, phosphatidate phosphohydrolase; CPT, carnitine palmitoyltransferase; SREBP1, sterol regulatory element-binding transcription factor 1; ACC, acetyl-CoA carboxylase; PPARα, peroxisome proliferator-activated receptor α; PGC1α, PPAR-γ coactivator 1 α.

Figure 4

Effect of eriodictyol treatment on the plasma glucose (A) and insulin (B) levels, HOMA-IR (C), glucose tolerance (D), plasma incretin hormones (E), activities of hepatic glucose-regulating enzyme (F), and expression levels of hepatic glucose-regulating genes in C57BL/6N mice fed with the high-fat diet (HFD). Data are presented as means ± SEM. Normal diet (ND; AIN-76) vs. HFD; ^* p < 0.05, ^*** p < 0.001. HFD vs. ED (HFD + 0.005% ED); ^§ p < 0.05, ^§§ p < 0.01, ^§§§ p < 0.001. HOMA-IR, homeostasis model assessment of insulin resistance; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; GK, glucokinase; PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6-phosphatase; PCK, PEPCK; G6PC, G6Pase; IRS2, insulin receptor substrate 2.

Figure 5

Effect of eriodictyol treatment on the plasma adipokine and cytokine levels in C57BL/6N mice fed with the high-fat diet (HFD). Data are presented as means ± SEM. Normal diet (ND; AIN-76) vs. HFD; ^* p < 0.05, ^** p <0.01, ^*** p < 0.001. HFD vs. ED (HFD + 0.005% ED); ^§ p < 0.05, ^§§ p < 0.01. PAI-1, plasminogen activator inhibitor-1; IFN-γ, interferon-gamma; IL, interleukin.