The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response

Abstract

Various models of mitochondrial stress result in induction of the stress-responsive cytokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). This is an adaptive mechanism downstream of the mitochondrial integrated stress response frequently associated with improvements in systemic metabolic health. Both FGF21 and GDF15 have been shown to modulate energy balance and glucose homeostasis, and their pharmacological administration leads to promising beneficial effects against obesity and associated metabolic diseases in pre-clinical models. Furthermore, endogenous upregulation of FGF21 and GDF15 is associated with resistance to diet-induced obesity (DIO), improved glucose homeostasis and increased insulin sensitivity. In this review, we highlight several studies on transgenic mouse models of mitochondrial stress and will compare the specific roles played by FGF21 and GDF15 on the systemic metabolic adaptations reported in these models.

Keywords: FGF21; GDF15; energy balance; integrated stress response; metabolic health; mitochondrial stress.

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).