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. 2018 Jun 16;19(6):1786.
doi: 10.3390/ijms19061786.

Quercetin Lowers Plasma Triglycerides Accompanied by White Adipose Tissue Browning in Diet-Induced Obese Mice

Eline N Kuipers  1   2 , Andrea D van Dam  3   4 , Ntsiki M Held  5 , Isabel M Mol  6   7 , Riekelt H Houtkooper  8 , Patrick C N Rensen  9   10 , Mariëtte R Boon  11   12
Affiliations

Quercetin Lowers Plasma Triglycerides Accompanied by White Adipose Tissue Browning in Diet-Induced Obese Mice

Eline N Kuipers et al. Int J Mol Sci. .

Abstract

Obesity and dyslipidemia are major risk factors for the development of cardiovascular diseases (CVD). Quercetin, a natural flavonoid, lowers plasma triglycerides (TG) in human intervention studies, and its intake is associated with lower CVD risk. The aim of this study was to elucidate the mechanism by which quercetin lowers plasma TG levels in diet-induced obesity. C57Bl/6J mice received a high-fat diet (45% of calories derived from fat) with or without quercetin (0.1% w/w) for 12 weeks. Quercetin decreased plasma TG levels from nine weeks onwards (−19%, p < 0.05), without affecting food intake, body composition, or energy expenditure. Mechanistically, quercetin did not reduce intestinal fatty acid (FA) absorption. Rather, quercetin induced a slight reduction in liver Apob expression (−13%, p < 0.05), which suggests decreased very-low density lipoprotein-TG production. Interestingly, quercetin also markedly increased the uptake of [³H]oleate, which was derived from glycerol tri[³H]oleate-labeled lipoprotein-like particles by subcutaneous white adipose tissue (sWAT, +60%, p < 0.05). Furthermore, quercetin also markedly increased mRNA expression of Ucp1 (+229%, p < 0.05) and Elovl3 (+138%, p < 0.05), specifically in sWAT. Accordingly, only quercetin-treated animals showed uncoupling protein-1 protein-positive cells in sWAT, which is fully compatible with increased browning. Taken together, the TG-lowering effect of quercetin may, at least in part, be due to increased TG-derived FA uptake by sWAT as a consequence of browning.

Keywords: brown adipose tissue; browning; obesity; quercetin; triglycerides; white adipose tissue.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Quercetin reduces plasma triglyceride levels without affecting body composition, food intake and energy expenditure. C57Bl/6J mice were fed a high-fat diet (HFD) +/− quercetin (0.1% w/w) for 12 weeks. Body weight was measured weekly (A). Body composition was determined (B). Plasma triglycerides were determined before and every three weeks during the intervention (C). Food intake was determined weekly (D). In the third week of treatment, animals were placed in fully automatic metabolic cages for an assessment of total energy expenditure (E), fat oxidation (F), and glucose oxidation (G). Data are represented as mean ± SEM (n = 8–10), * p < 0.05 versus control.
Figure 2
Figure 2
Quercetin reduces hepatic apolipoprotein B (Apob) expression and increases the uptake of triglycerides (TG)-derived fatty acid (FA) by subcutaneous white adipose tissue. In week 2 and week 10 of the intervention, 24 h feces was collected (A) and used to determine fecal free fatty acid (FFA) concentration (B). Gene expression in the liver was determined by qRT-PCR for acyl-CoA synthetase long-chain family member 1 (Acsl1), acetyl-CoA carboxylase 2 (Acc2), microsomal triglyceride transfer protein (Mttp), and Apob (C). After 12 weeks, mice were injected with glycerol tri[3H]oleate-labeled lipoprotein-like particles, and clearance from plasma (D) and uptake per gram organ (E) were determined by 3H-activity analysis. Data are represented as mean ± SEM (n = 8–10); the expression of genes was corrected for the reference gene β2-microglobulin, * p < 0.05, ** p < 0.01, *** p < 0.001 versus control. (g,s,v)WAT: gonadal, subcutaneous, visceral white adipose tissue; (i,s)BAT: interscapular, subscapular brown adipose tissue; qua: quadriceps muscle; sol: soleus muscle.
Figure 3
Figure 3
Quercetin increases uncoupling protein-1 (Ucp1) gene expression specifically in subcutaneous white adipose tissue. Gene expression in sWAT (A) and BAT (B) was determined by qRT-PCR. Hematoxylin and eosin (H&E) staining was performed on paraffin-embedded sWAT sections, and representative pictures are shown (C). Pictures were analyzed in ImageJ to determine the relative cell size (D). sWAT sections were stained for UCP-1 (arrows indicate UCP-1 positive cells, E) as well. BAT sections were stained for H&E (F) and used to quantify lipid droplet content in ImageJ (G). BAT sections were also stained for UCP-1 (H). Data are represented as mean ± SEM (n = 8–10); the expression of genes was corrected for the reference gene β2-microglobulin (sWAT), Gapdh, and Hprt (BAT), * p < 0.05 versus control. Bars (C,E,F,H) indicate 200 µm.
Figure 4
Figure 4
Proposed mechanism by which quercetin lowers plasma triglycerides (TG). Plasma TG levels are regulated by intestinal TG absorption, hepatic very-low density lipoprotein (VLDL)-TG production, and the clearance of TG-derived fatty acids (FA) by peripheral organs such as sWAT in a process that is dependent on lipoprotein lipase (LPL) (A). Quercetin induces the browning of sWAT, resulting in an increased uptake of TG-derived FA by sWAT. This may contribute to the lowering of plasma TG levels. Moreover, quercetin may also lower lipolysis from sWAT, which may contribute to lower plasma free FA (FFA) levels and lower VLDL-TG production by the liver, also contributing to lower plasma TG levels. Lastly, quercetin increases the uptake of lipids by the intestine, which apparently does not counteract the reduction in plasma TG levels (B). Bold arrows indicate increased flux; dashed arrows indicate decreased flux. LDLr: low-density lipoprotein receptor; LRP: low-density lipoprotein receptor-related protein.
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