Abstract
BACKGROUND: Obesity can play a role in the development of hepatic insulin resistance. Although the molecular mechanism of the association between obesity and hepatic insulin resistance is unclear, it has been reported that obesity leads to hepatic endoplasmic reticulum (ER) stress and inflammation, which can induce the development of insulin resistance in several tissues. OBJECTIVE: In this study, we investigated the associations between hepatic insulin resistance, ER, and inflammation in obesity and the effect of water extract from Cudrania tricuspidata leaves (CTL) on hepatic insulin resistance induced by ER stress and inflammation in db/db mice. DESIGN: The mice were randomly divided into four groups: a normal control group (C57BL/6J), a control group (C57BL/6J-db/db), a CTL 100 group (C57BL/6J-db/db mice fed a dietary supplement of 100 mg/kg of CTL), and a CTL 300 group (C57BL/6J-db/db mice fed a dietary supplement of 300 mg/kg of CTL). After 8 weeks, we performed an oral glucose tolerance test and the mice were sacrificed. RESULTS: The C57BL/6J-db/db mice developed obesity and hyperglycemia, and the ER stress response and inflammation were activated in their livers. Interestingly, there was a marked decrease in the activation of the ER stress response and insulin resistance in the livers of the C57BL/6J-db/db mice treated with CTL due to decreases in the phosphorylation of eIF2α, IRE1α, and IRS-1 serine and decreases in the mRNA expression of ATF4, c-Jun N-terminal kinase, C/EBPα, and C/EBP homologous protein. Dietary supplementation with CTL also induced a statistically significant decrease in the expression of pro-inflammatory cytokines, C-reactive protein (CRP), and NF-κB phosphorylation. CONCLUSIONS: Overall, these results suggest that CTL can improve hepatic insulin resistance and hyperglycemia by controlling obesity-induced ER stress and inflammation in the liver and that CTL may be a useful agent in treating hyperglycemia.