Given that PAI-1 is dramatically up-regulated in human obesity (Ma et al., 2004), and can be increased by high fat feeding (1–6 weeks) of normal weight subjects, we hypothesized that PAI-1 contributes to macrophage-mediated inflammation in AT and metabolic dysfunction in a HFD-induced obese mouse model. Here, SERPINE1 is linked to obesity due to melanocortin 4 receptor deficiency.