In addition to the tissue-specific responses to FGF21-stimulated adipocyte signals that alter metabolism to reduce tissue stress, the mechanisms that control the induction of FGF21 in specific tissues in crisis also requires clarification (Table 1). Multiple transcription factors including nuclear receptors have been implicated in control of FGF21 expression in different tissues. Some of them are involved in the intrinsic cellular stress-responsive pathways, such as the SREBP1c and ATF4 in the ER stress response that are associated with the Golgi, peroxisome (53, 57), and mitochondria and involved in lipid, energy, and glucose metabolism. Future studies may reveal novel tissue-specific FGF21-mediated stress response pathways and mechanisms.
