Deficiency of circadian gene Per2 blocks luteolin-induced adipocyte browning in mice through weakening liver PPARα/RXRα/FGF21 pathway

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.