Notably, whether hypothalamic inflammation and associated ER stress and autophagy disorders, which have been extensively linked with diet-induced obesity, are causative or a consequence of leptin resistance is yet to be determined (Figure 2) (Souza et al. 2005; Thaler et al. 2013; Zhang & Kaufman 2008). Here, LEP is linked to obesity due to melanocortin 4 receptor deficiency.