7A), verifying the improvement of insulin signaling. Consistently, treatment of H4IIE cells with IsoLQ (5-20 μM) or LQ (10-100 μM) effectively prevented the serine phosphorylation http://www.selleckchem.com/products/CAL-101.html of IRS1 (Fig. 7B). The inhibition of IRS1 serine phosphorylation by IsoLQ or LQ was also confirmed in other cell models such as HepG2 cells, C2C12 myotubes, 3T3-L1 adipocytes, and primary rat hepatocytes (Fig. 7C). To further assess
the effect of IsoLQ or LQ on glucose homeostasis and insulin sensitivity, each agent was administered to mice fed an HFD: treatment of mice with the agents at the dose of 10 or 30 mg/kg/day for 5 days during the last 5 weeks of total 11 weeks of HFD feeding displayed a significantly improved glucose tolerance (2
g glucose/kg) compared to vehicle-treated control (Fig. 8A; normal diet [ND] and HFD controls were shared to simultaneously compare the compound effects), showing their effects on systemic insulin sensitivity. In mice fed an HFD for 9 weeks, IsoLQ treatment almost completely reduced fasting glucose, fasting serum insulin levels, and HOMA-IR values (Fig. 8B, upper). Similar results were obtained using Lepob/ob mice (Fig. 8B, lower). Our results indicate that licorice flavonoids have the ability to reduce obesity-induced insulin resistance. As a continuing effort to assess the effect of IsoLQ or LQ on insulin action, we measured glucose production and uptake in representative cell models. Incubation of HepG2 cells with each agent resulted in a significant decrease in glucose production, which IWR-1 research buy was comparable to that caused by insulin (Fig. 8C, left). TNF-α inhibited an increase in glucose uptake by insulin in C2C12 myotubes or differentiated 3T3-L1 adipocytes, which was also abrogated by IsoLQ treatment (Fig. 8C, middle and right). Our results indicate that IsoLQ (or LQ) treatment prevents glucose production from hepatocytes and stimulates glucose uptake into selleckchem muscle
cells or adipocytes. In HFD-fed mice, we measured the levels of glucose 6-phosphatase (G6Pase) mRNA as a marker of gluconeogenesis. IsoLQ or LQ treatment inhibited the G6Pase gene induction (Fig. 8D, upper). Consistently, either IsoLQ or LQ treatment antagonized the ability of cyclic adenosine monophosphate (cAMP) and dexamethasone to increase G6Pase mRNA levels in primary rat hepatocytes, as did insulin (Fig. 8D, lower). These results demonstrate that the inhibition of glucose production by IsoLQ or LQ may be mediated by the suppression of G6Pase. PTP1B negatively regulates insulin signaling by catalyzing the dephosphorylation of IR and IRS1/2.5 A decrease in PTP1B activity accompanies improved insulin sensitivity in obese subjects.18 In addition, evidence is accumulating that PTP1B polymorphisms in humans might be associated with insulin resistance.