Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Lee JY

PROVIDER: S-EPMC8640151 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ObjectiveCelastrol was recently identified as a potential novel treatment for obesity. However, the effect of Celastrol on nonalcoholic fatty liver disease (NAFLD) remains elusive. The aim of this study is to evaluate the role of Celastrol in NAFLD.MethodsFunctional studies were performed using wild-type C57BL/6J (WT) mice and liver specific Sirt1-deficient (LKO) mice. The molecular mechanism was explored in primary mouse liver and primary hepatocytes.ResultsWhen WT mice receiving a high-fat diet (HFD) were treated with Celastrol, reductions in body weight, subcutaneous and visceral fat content, and liver lipid droplet formation were observed, along with reduced hepatic intracellular triglyceride and serum triglyceride, free fatty acid, and ALT concentrations. Furthermore, Celastrol decreased hepatic sterol regulatory element binding protein 1c (Srebp-1c) expression, enhanced the phosphorylation of hepatic AMP-activated protein kinase α (AMPKα), and increased the expression of hepatic serine-threonine liver kinase B1 (LKB1). Additionally, Celastrol treatment improved glucose tolerance and insulin sensitivity in WT mice fed the HFD. Celastrol administration also improved the anti-inflammatory and anti-oxidative status by inhibiting nuclear factor kappa B (NFκB) activity and the mRNA levels of proinflammatory cytokines and increasing mitochondrial DNA copy number and anti-oxidative stress genes expression in WT mice liver, in vivo and in vitro. Moreover, Celastrol induced hepatic Sirt1 expression in WT mice, in vivo and in vitro. These Celastrol-mediated protective effects in WT mice fed a HFD were abolished in LKO mice fed a HFD. It was more interesting that Celastrol aggravated HFD-induced liver damage in LKO mice fed a HFD by inhibiting the phosphorylation of AMPKα and boosting the translocation of NFκB into the nucleus, thereby resulting in the increase of Srebp-1c expression and the mRNA levels of liver proinflammatory cytokines.ConclusionsCelastrol ameliorates NAFLD by decreasing lipid synthesis and improving the anti-oxidative and anti-inflammatory status. And Sirt1 has an important role in Celastrol-ameliorating liver metabolic damage caused by HFD.