Interleukin 18 (IL18)-Na-Cl cotransporter (NCC) signaling triggers β cell proliferation, development survival and insulin production in islets. Targeting islet insulin production is a potential strategy for hyperglycemia treatment. Dietary flavonoids possess the substantial anti-hyperglycemia activity. However, whether these flavonoids improve hyperglycemia through directly promoting islet insulin production and the underlying mechanism remains unclear. In this study, islets are isolated from wild-type (WT) and Ncc^-/- mice and treated with dietary flavonoids ex vivo. Among the six dietary flavonoids of chrysin, apigenin, luteolin, quercetin, myricetin and kaempferol, 10 μM luteolin and kaempferol exhibit the highest activities in stimulating insulin production in ex vivo islet. Furthermore, luteolin and kaempferol treatments increase IL18 production and NCC expression, enhance β cell proliferation and survival, protect against streptozocin (STZ)-induced apoptosis and damage in islet. However, the deficiency of NCC eliminate these activities of luteolin and kaempferol. Moreover, STZ-induced hyperglycemic mice are fed a diet supplemented with 0.01% luteolin or kaempferol. In vivo studies have shown that dietary supplementation with luteolin or kaempferol improves glucose tolerance and insulin production, alleviates the apoptosis of islet β cells, and elevates IL18 expression in STZ-induced hyperglycemic mice. In conclusion, dietary luteolin and kaempferol promote islet insulin production, proliferation and survival, protect against STZ-induced islet apoptosis and hyperglycemia through IL18-NCC signaling.

During the development of diet-induced obesity, the change of energy matebolism is closely related to the function of the circadian clock in mammals. Luteolin (LU), one of the most common natural flavonoids riched in many edible plants, can ameliorate obesity by activating adipose tissue browning, but its effect on circadian clock in this process remains poorly understood. Here we found that dietary LU improved circadian misalignment of energy expenditure in high-fat diet (HFD)-fed wild-type (WT) mice. Moreover, dietary LU efficiently elevated uncoupling protein 1 levels in adipose tissue during the dark period, which was similar to the LU-increased hepatic PER2 expressions. Hepatic peroxisome proliferators-activated receptors α (PPARα)/recombinant retinoid X receptor α (RXRα)/fibroblast growth factor 21 (FGF21) pathway was rhythmically elevated by dietary LU in HFD-fed WT mice, whereas the promotion was inhibited in Per2^-/- mice. Meanwhile, Per2 deletion abolished the effects of dietary LU on adipose tissue browning in HFD-fed mice. Further, LU treatment directly activated PPARα/RXRα/FGF21 signaling in primary cultured hepatocytes from WT mice rather than Per2^-/- mice. Taken together, the deletion of the core clock component Per2 impedes LU-induced adipose tissue browning through weakening PPARα/RXRα/FGF21 pathway in mice, providing a new insight into the interplay of energy metabolism and circadian clock for the anti-obesity activity of LU.