Lastly, evidences from experimental and clinical studies demonstrated that SHBG is downregulated by pro-inflammatory cytokines, such as TNF-a and IL-1b (39), therefore suggesting that these factors might play a role in the reduction of SHBG levels in chronic inflammatory diseases, such as obesity and diabetes, characterized by increased levels of pro-inflammatory cytokines. This evidence concerns the gene SHBG and obesity due to melanocortin 4 receptor deficiency.