INS and obesity due to melanocortin 4 receptor deficiency: Indeed, the knock-out mouse was first generated years ago (Buhr et al., 2015), but it has just recently been discovered that only when perturbing normal living and physiological conditions does the OPN3 knock-out mouse exhibit diet-induced obesity and insulin resistance because of dysregulation of metabolic processes in brown adipocytes (Sato et al., 2020) and deficiency in thermogenesis under cold shock because of dysregulation of lipolysis in adipose tissue (Nayak et al., 2020).