TNF and obesity due to melanocortin 4 receptor deficiency: In 2018, Nagahashi et al. investigated the link among obesity, inflammation and cancer and confirmed that in breast cancer patients and animal models the HFD, alone was able to induce the axis SphK1/S1P/S1PR1 and to stimulate in obesity a cancer-associated pro-inflammatory cytokines (IL-6 and TNF-α) [161].