TM6SF2 and obesity due to melanocortin 4 receptor deficiency: The proximal cause for many of these abnormalities is obesity-induced insulin resistance, in response to environmental factors (sedentary lifestyle or nutrient overload such as high-fat, high-carbohydrate, or high-fructose diets) that exacerbate underlying genetic predisposition (such as single nucleotide polymorphisms of patatin-like phospholipase domain containing protein 3 (Pnpla3) or transmembrane 6 superfamily member 2 (Tm6sf2), leading to hepatic lipid accumulation (Figure 1).