In support of this model, NRF2 activation through skeletal muscle-specific ablation of KEAP1 protects from the development of diet-induced obesity and metabolic syndrome in wild-type mice with a significantly compromised effect in Leprdb/db mice (Uruno et al., 2016; Matzinger et al., 2018), emphasizing the cell-nonautonomous connection between muscle NRF2 action and central leptin signaling. Here, LEP is linked to metabolic syndrome.