Figure 5 summarizes the conceptual framework of proximal inter-tissue crosstalk mediators in lipid metabolism among different connective tissues in obesity and T2DM. The following subsections detail these mediators and the mechanisms underlying their local interactions. An extended thematic summary of the crosstalk mediators, including their principal effects on lipid metabolism and insulin signaling are also provided in Supplementary Table S1. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.