Reduced ratio of pSmad/Smad in PDE3B−/−WAT (Fig. 4C) suggest that PDE3B regulation of TGF-β/smad signaling may play a role in the effects of smad signaling in the pathogenesis of obesity, inflammation and development of insulin resistance. This evidence concerns the gene TGFB1 and obesity due to melanocortin 4 receptor deficiency.