These studies suggests that the activation of FGF21 in liver, muscle, and other tissues is a response of these tissues and organs to stress triggered by external challenge and internal cellular pathogenesis that lead to defects in metabolic homeostasis. In support of this notion, several nuclear receptors and transcription factors that are involved in metabolic stress responses regulate FGF21 expression. These include PPARα/γ, RAR, ChREBP, SREBP1c, LXR, STAT3/5, p53, and ATF4 (9, 16, 26, 33–39). The question is why these organs when under stress use FGF21 as a systemic alarm signal.
