The PGC-1α/ERRα and PGC-1α/PPARα axes act as bridges connecting AMPK and NRF1/2 to promote mitochondrial biogenesis and increase mitochondrial density in muscle training, obesity, sarcopenia, and environmental exposures by inducing TFAM transcription, which is primarily targeted to aerobic and endurance exercise. Here, PPARGC1A is linked to obesity due to melanocortin 4 receptor deficiency.