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Ipragliflozin, an SGLT2 Inhibitor, Ameliorates High-Fat Diet-Induced Metabolic Changes by Upregulating Energy Expenditure through Activation of the AMPK/ SIRT1 Pathway

 Ji-Yeon Lee  ;  Minyoung Lee  ;  Ji Young Lee  ;  Jaehyun Bae  ;  Eugene Shin  ;  Yong-Ho Lee  ;  Byung-Wan Lee  ;  Eun Seok Kang  ;  Bong-Soo Cha 
 DIABETES & METABOLISM JOURNAL, Vol.45(6) : 921-932, 2021-11 
Journal Title
Issue Date
Adipose tissue ; Obesity ; Sodium-glucose transporter 2 inhibitors ; Thermogenesis
Background: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that exhibit multiple extraglycemic effects. However, there are conflicting results regarding the effects of SGLT2 inhibition on energy expenditure and thermogenesis. Therefore, we investigated the effect of ipragliflozin (a selective SGLT2 inhibitor) on energy metabolism.

Methods: Six-week-old male 129S6/Sv mice with a high propensity for adipose tissue browning were randomly assigned to three groups: normal chow control, 60% high-fat diet (HFD)-fed control, and 60% HFD-fed ipragliflozin-treated groups. The administration of diet and medication was continued for 16 weeks.

Results: The HFD-fed mice became obese and developed hepatic steatosis and adipose tissue hypertrophy, but their random glucose levels were within the normal ranges; these features are similar to the metabolic features of a prediabetic condition. Ipragliflozin treatment markedly attenuated HFD-induced hepatic steatosis and reduced the size of hypertrophied adipocytes to that of smaller adipocytes. In the ipragliflozin treatment group, uncoupling protein 1 (Ucp1) and other thermogenesis-related genes were significantly upregulated in the visceral and subcutaneous adipose tissue, and fatty acid oxidation was increased in the brown adipose tissue. These effects were associated with a significant reduction in the insulin-to-glucagon ratio and the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway in the liver and adipose tissue.

Conclusion: SGLT2 inhibition by ipragliflozin showed beneficial metabolic effects in 129S6/Sv mice with HFD-induced obesity that mimics prediabetic conditions. Our data suggest that SGLT2 inhibitors, through their upregulation of energy expenditure, may have therapeutic potential in prediabetic obesity.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Bae, Jae Hyun(배재현) ORCID logo https://orcid.org/0000-0002-3462-890X
Lee, Minyoung(이민영) ORCID logo https://orcid.org/0000-0002-9333-7512
Lee, Byung Wan(이병완) ORCID logo https://orcid.org/0000-0002-9899-4992
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Lee, Ji Yeon(이지연)
Cha, Bong Soo(차봉수) ORCID logo https://orcid.org/0000-0003-0542-2854
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