(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics; quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence; glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.
- MeSH
- aplikace orální MeSH
- benzhydrylové sloučeniny aplikace a dávkování MeSH
- buňky 3T3-L1 MeSH
- buňky Hep G2 MeSH
- down regulace účinky léků MeSH
- dyslipidemie farmakoterapie MeSH
- glifloziny aplikace a dávkování MeSH
- glukoneogeneze účinky léků genetika MeSH
- glukosidy aplikace a dávkování MeSH
- hmotnostní přírůstek účinky léků MeSH
- hypertriglyceridemie farmakoterapie metabolismus MeSH
- hypoglykemika aplikace a dávkování MeSH
- inzulinová rezistence MeSH
- játra metabolismus MeSH
- krysa rodu rattus MeSH
- ledviny metabolismus MeSH
- lidé MeSH
- lipogeneze účinky léků genetika MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- oxidační stres účinky léků MeSH
- stárnutí buněk účinky léků MeSH
- tuková tkáň metabolismus MeSH
- upregulace účinky léků MeSH
- viabilita buněk účinky léků MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15-month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF-α and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-α signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.
- MeSH
- C-reaktivní protein biosyntéza genetika MeSH
- geneticky modifikovaná zvířata genetika MeSH
- hnědá tuková tkáň metabolismus MeSH
- hypertenze farmakoterapie genetika patologie MeSH
- inzulinová rezistence genetika MeSH
- játra metabolismus MeSH
- krysa rodu rattus MeSH
- kyseliny mastné neesterifikované metabolismus MeSH
- lidé MeSH
- metabolický syndrom farmakoterapie genetika patologie MeSH
- metabolismus lipidů účinky léků MeSH
- NLR proteiny biosyntéza MeSH
- oxidační stres účinky léků MeSH
- PPAR alfa biosyntéza MeSH
- salicylany aplikace a dávkování MeSH
- TNF-alfa biosyntéza MeSH
- zánět farmakoterapie genetika patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
