Large fat cells in obesity may have restricted capacity to take up excess fatty acid because of: (i) low adipogenic transcription factor expression and consequently impaired machinery to process fatty acids; (ii) insulin resistance with inhibition of IRS-1 and Glut-4; (iii) increased lipolysis with fatty acid release owing to insulin resistance; (iv) instability from their large size, with increased risk of apoptosis/necrosis; and (v) high fat tissue concentrations of TNFα [which is lipolytic and anti-adipogenic; (Cinti et al., 2005; Xie et al., 2006; Gustafson et al., 2009)]. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.