Recent evidence suggests that
troxerutin, a trihydroxyethylated derivative of natural
bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of
troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD +
Troxerutin group, and
Troxerutin group.
Troxerutin was treated by daily
oral administration at doses of 150 mg/kg/day for 20 weeks.
Tauroursodeoxycholic acid (
TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that
troxerutin effectively improved
obesity and related metabolic parameters, and liver
injuries in HFD-treated mouse. Furthermore,
troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover,
troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory
cytokines in HFD-treated mouse livers. Mechanismly,
troxerutin dramatically decreased
Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by
TUDCA treatment. These improvement effects of
troxerutin on hepatic
glucose disorders might be mediated by its anti-
obesity effect. In conclusion,
troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent
inflammation, which might be mediated by its anti-
obesity effect.