Dexamethasone synergizes with high-fat diet to increase lipid deposition in adipocytes

Abstract

Background/aims: Dexamethasone (DEX) is a widely used exogenous therapeutic glucocorticoid in clinical settings. Its long-term use leads to many side effects. However, its effect on metabolic disorders in individuals on a high-fat diet (HFD) remains poorly understood.

Methods: In this study, HFD-fed mice were intraperitoneally injected with DEX 2.5 mg/kg/day for 30 days. Lipid metabolism, adipocyte proliferation, and inflammation were assayed using typical approaches.

Results: DEX increased the epididymal fat index and epididymal adipocyte size in HFD-fed mice. The number of epididymal adipocytes with diameters > 70 μm accounted for 0.5% of the cells in the control group, 30% of the cells in the DEX group, 19% of the cells in the HFD group, and 38% of all the cells in the D+H group. Adipocyte proliferation in the D+H group was inhibited by DEX treatment. Adipocyte enlargement in the D+H group was associated with increased the lipid accumulation but not the adipocyte proliferation. In contrast, the liver triglyceride and total cholesterol levels and their metabolism were downregulated by the same treatment, indicating the therapeutic potential of DEX for nonalcoholic fatty liver disease.

Conclusion: DEX synergizes with HFD to promote lipid deposition in adipose tissues. A high risk of obesity development in patients receiving HFD and DEX treatment is suggested.

Keywords: Dexamethasone; High-fat diet; Nonalcoholic fatty liver disease; Obesity.

Figure 1

Body weight, food intake, and blood lipid levels during the 30-day DEX treatment. (A) Body weight changes in different groups. (B) Food intake trends in different groups. (C, D) Plasma TC and TG levels in each group. The Con group was intraperitoneally injected with saline only. The mice in the DEX group were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM. HFD mice were fed HFD. D+H mice were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM and fed HFD. Data are expressed as mean ± standard deviation. HFD, high-fat diet; DEX, dexamethasone; D+H, DEX + HFD; TC, total cholesterol; TG, triglyceride. *Indicated p < 0.05, in comparison between DEX and Con groups. ^#Indicated p < 0.05, in comparison between D+H and HFD groups.

Figure 2

Effect of DEX treatment on epididymal AW, epididymal fat index, epididymal fat lipid levels, and epididymal adipocyte size in mice. (A) AW changes in each group. (B) AW/BW changes in each group. (C, D) Adipose TG and TC levels in mice. (E–H) H&E staining of mouse epididymal adipose tissues (400×), scale bar = 25 μm. Histogram of adipocyte distribution of different diameters in epididymal adipose tissues of the (I) Con group, (J) DEX group, (K) HFD group, and (L) D+H group. The Con group was intraperitoneally injected with saline only. The mice in the DEX group were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM. HFD mice were fed HFD. D+H mice were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM and fed HFD. Data are expressed as mean ± standard deviation. DEX, dexamethasone; HFD, high-fat diet; D+H, DEX + HFD; AW, adipose weight; BW, body weight; TG, triglyceride; TC, total cholesterol. *Indicated p < 0.05, difference among groups.

Figure 3

Effect of DEX treatment on lipid metabolism, the expression of proliferation-related proteins and genes in epididymal adipose tissues of mice. (A–C) Relative mRNA levels of Fabp4, Angptl8, and Fasn. (D–G) Protein expression and densitometric analysis of PCNA, YAP, P-YAP, and GAPDH in each group. (H–J) mRNA expression of Ki67, Pcna and Cyclin B2 in different groups. The Con group was intraperitoneally injected with saline only. The mice in the DEX group were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM. HFD mice were fed HFD. D+H mice were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM and fed HFD. Data are expressed as mean ± standard deviation. DEX, dexamethasone; HFD, high-fat diet; D+H, DEX + HFD. *Indicated p < 0.05, difference among groups.

Figure 4

Effects of DEX treatment on lipid content and, lipid metabolism in liver tissues. (A) LW changes in different groups. (B) LW/BW ratio changes in each group. (C, D) Liver TG and TC levels in each group. (E–H) H&E staining of mouse epididymal adipose tissues (400×), scale bar = 25 μm. Fatty vacuoles in liver tissue are represented by white arrows. (I–L) mRNA expression of lipid metabolism (Fabp1, Plin2, Angptl8, and Hsl) in different groups. The Con group was intraperitoneally injected with saline only. The mice in the DEX group were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM. HFD mice were fed HFD. D+H mice were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM and fed HFD. Data are expressed as mean ± standard deivaiton. DEX, dexamethasone; HFD, high-fat diet; D+H, DEX + HFD; LW, liver weight; BW, body weight. *Indicated p < 0.05, difference among groups.

Figure 5

Effects of DEX treatment on inflammation in the liver. (A–D) mRNA expression of inflammatory factors (Il-1β, Ccl2, Tnf-α, and Il-2) in each group. The Con group was intraperitoneally injected with saline only. The mice in the DEX group were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM. HFD mice were fed HFD. D+H mice were intraperitoneally injected with DEX 2.5 mg/kg once daily at 09:00 AM and fed HFD. Data are expressed as mean ± standard deviation. DEX, dexamethasone; HFD, high-fat diet; D+H, DEX + HFD. *Indicated p < 0.05, difference among groups.