Figure 1.

Summary of FGF21 and GDF15 mediated actions downstream of mitochondrial stress. Mitochondrial stress of various etiologies and in various tissues lead to the activation of stress response pathways such as the mtUPR and the ISR, resulting in the translation of transcription factors such as ATF4 and its downstream target CHOP, which promote induction of FGF21 and GDF15, respectively. Secretion of these factors into the circulation mediates metabolic adaptations in response to mitochondrial stress. Together, these adaptations promote improvements in systemic metabolic health, including increases in energy expenditure, resistance to diet-induced obesity (DIO), improved insulin sensitivity and glucose homeostasis, attenuated hepatic steatosis, and increased browning. Abbreviations: WAT (white adipose tissue), BAT (brown adipose tissue), UPR^mt (mitochondrial unfolded protein response), ISR (integrated stress response), ATF4 (activating transcription factor 4), CHOP (C/EBP homologous protein), FGF21 (fibroblast growth factor 21) and GDF15 (growth differentiation factor 15).