Nrf2 induces fibroblast growth factor 21 in diabetic mice

Transcription factor N rf2 (nuclear factor E 2‐related factor 2) is a master regulator of cellular defense system against oxidative and electrophilic stresses and is negatively regulated by an adaptor protein K eap1 ( K elch‐like ECH ‐associated protein 1). Nrf2 also plays a pivotal role in metabolic homeostasis, such as lipid metabolism and energy expenditure as well as redox homeostasis. FGF 21 (fibroblast growth factor 21) is known as a key mediator of glucose and lipid metabolism. Here, we found that N rf2 is involved in FGF 21 regulation in diabetic model mice. N rf2 induction by genetic knockdown of K eap1 increased plasma FGF 21 level and hepatic F gf21 expression in diabetic db/db mice and high‐calorie‐diet‐induced obesity model mice. Administration of CDDO ‐ I m (oleanolic triterpenoid 1‐[2‐cyano‐3,12‐dioxooleane‐1, 9(11)‐dien‐28‐oyl] imidazole), a potent N rf2 inducer, up‐regulated plasma FGF 21 level and hepatic F gf21 expression in db/db mice, whereas CDDO ‐ I m did not induce FGF 21 in db/db mice with N rf2 knockout background. Furthermore, in K eap1 ‐knockdown db/db mice, N rf2 enhanced expression of glucose‐ and lipid‐metabolism‐related genes in adipose tissues, which improved plasma lipid profiles. These results show that N rf2 positively regulates FGF 21 expression in diabetic mice. We propose that FGF 21 is a potential efficacy biomarker that mediates metabolic regulation by the K eap1– N rf2 system.