This “second hit” may be conditions of metabolic stresses such as physical inactivity, chronic inflammation, or presence of a pre-existing cardiometabolic disease (e.g., obesity), and it may implicate downregulated NAMPT (Costford et al., 2010, Imai and Yoshino, 2013), depressed hepatic NADP(H) (Trammell et al., 2016b), and/or activation of CD38 (Camacho-Pereira et al., 2016, Covarrubias et al., 2019). This evidence concerns the gene CD38 and obesity due to melanocortin 4 receptor deficiency.