We used data from a case–control study nested within the International Breast Cancer Intervention Study II (IBIS-II) [18,19] to conduct a mediation analysis investigating whether the association between BMI, as a measure of obesity, and postmenopausal breast cancer risk is mediated by adiponectin or other hormonal, metabolic, and inflammatory biomarkers (leptin, IGF-I, IGF-binding protein 1 (IGFBP1), high-sensitivity C-reactive protein (hs-CRP), glycemia, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index, and SHBG). This evidence concerns the gene ADIPOQ and obesity due to melanocortin 4 receptor deficiency.