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. 2024 Mar 19;25(1):26.
doi: 10.1186/s40360-024-00747-5.

Dapagliflozin promotes white adipose tissue browning though regulating angiogenesis in high fat induced obese mice

Lin Xiang  1 , Min Liu  1 , Guangda Xiang  1 , Ling Yue  1 , Junxia Zhang  1 , Xiaoli Xu  2   3 , Jing Dong  4
Affiliations

Dapagliflozin promotes white adipose tissue browning though regulating angiogenesis in high fat induced obese mice

Lin Xiang et al. BMC Pharmacol Toxicol. .

Abstract

Browning of white adipose tissue (WAT) is become an appealing target for therapeutics in the treatment of obesity and related metabolic diseases. Dapagliflozin is widely used in the treatment of type 2 diabetes, and it is also found that the drug exhibits regulate systemic metabolism such as obesity, insulin resistance and hepatic steatosis. However, the precise role of dapagliflozin on WAT remodeling remains to be elucidated. The current study aimed to explore the role of dapagliflozin on WAT browning in high-fat diet (HFD)-induced obese mice. Male C57BL/6J mice (n = 6 per group) were used to establish obesity model by following feeding with HFD for 6 weeks. The mice were randomly treated with or without dapagliflozin for the experimental observation. The volume and fat fraction of WAT were quantified, H&E, UCP-1 staining and immunohistochemistry were conducted to investigate the white-to-brown fat conversion and angiogenesis in WAT respectively. Quantitative real-time polymerase chain reaction (qPCR) was employed to explore the mRNA expression levels of genes related to fat browning and angiogenesis in WAT. Subsequently, 3T3-L1 cells were used to explore the effect of dapagliflozin on preadipocytes differentiation in vitro. Our results demonstrated that dapagliflozin could reduce body weight gain and promote WAT browning in HFD induced obese mice via regulating lipogenesis and angiogenesis in WAT. Furthermore, dapagliflozin reduce cells differentiation, up-regulate the expression of WAT browning and angiogenesis genes in 3T3-L1 adipocytes in vitro. In conclusion, dapagliflozin can potentially promote WAT browning in HFD induced obese mice via improving lipogenesis and angiogenesis in WAT.

Keywords: Adipocytes; Dapagliflozin; Obesity; White adipose tissue browning.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Effects of dapagliflozin on body weight and glycolipid metabolism in mice. (A) Schematic study plan. 4–5 weeks old, male C57BL/6 mice with similar body weights were fed with normal chow diet (CD) or high fat diet (HFD). After 6weeks, mice in HFD + Dapa group were intragastrically administered with 1 mg /kg /day dapagliflozin (Dapa) for 9 weeks, mice in other groups were treated with 0.5% sodium carboxyl methyl cellulose solution as controls. (B) Body weight change. (C) The effect of 9 weeks of intragastric administration of Dapa on food intake. (D) Liver weight. (E) Levels of fasting blood glucose (FBG). (F–H) Levels of insulin, FFA and TG in serum. (n = 5). Values are mean ± SEM. *, P < 0.05
Fig. 2
Fig. 2
Dapagliflozin improves lipogenesis and induces white adipose tissue (WAT) browning in mice. (A-C) Representative images and weight of iWAT and eWAT in different groups. (D-F) H&E staining of iWAT and eWAT (Scar bar 100 μm) and the size of adipocytes in different groups. (G-I) Immunohistochemical staining of iWAT and eWAT (Scar bar 100 μm) and relative expression of UCP-1 in different groups. (J) Relative mRNA expression of lipogenesis -related genes in WAT. (K) Relative mRNA expression levels of brown gene in WAT. (n = 5). Values are mean ± SEM. *, P < 0.05
Fig. 3
Fig. 3
Dapagliflozin regulates adipose tissue angiogenesis in WAT. (A-B) Representative immunofluorescence images and relative and relative fluorescence intensive level of CD31 in WAT from different group mice. Scar bar 50 μm. (C-D) Relative mRNA expression of VEGFA and PRDM16 in WAT from different group mice. (n = 5). Values are mean ± SEM. *, P < 0.05
Fig. 4
Fig. 4
Dapagliflozin reduced the differentiation of 3T3-L1 preadipocytes. (A) The effect of dapagliflozin on cell viability. (B) H&E staining of adipocytes under different concentration PA intervention. (C) Oil Red O staining of differentiated adipocytes. (D) Relative lipid accumulation in different group cells as examined by measuring absorbance at 540 nm of Oil Red O staining. (E-G) Relative mRNA expression of lipogenesis -related genes in cells. Values are mean ± SEM. *P < 0.05. Each experiment in vitro was repeated 3 times
Fig. 5
Fig. 5
Dapagliflozin regulated genes expression of WAT browning and angiogenesis in adipocytes in vitro. (A) Representative WB images and the protein levels of UCP-1 and PCG-1α. (B-C) Relative mRNA expression levels of brown gene in 3T3-L1 cells (D) Relative mRNA expression levels of VEGFA in 3T3-L1 cells. Values are mean ± SEM. *P < 0.05. Each experiment in vitro was repeated 3 times
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