Over the past years we have embarked in a systematic analysis of the effect of obesity or fatty acids on circulating monocytes, microvascular endothelial cells, macrophages and skeletal muscle cells. Using cell culture strategies, we have deconstructed complex physiological systems, then reconstructed 'partial equations' to better understand cell-to-cell communication. Through these approaches we identified that in high saturated fat environments, cell-autonomous pro-inflammatory pathways are activated in monocytes and endothelial cells, promoting monocyte adhesion and transmigration. We think of this as a paradigm of the conditions promoting immune cell infiltration into tissues during obesity. In concert, it is possible that muscle and adipose tissue secrete immune cell chemoattractants, and indeed our tissue culture reconstructions reveal that myotubes treated with the saturated fatty acid palmitate, but not the unsaturated fatty acid palmitoleate, release nucleotides that attract monocytes, and other compounds that promote pro-inflammatory 'M1-like' polarization in macrophages. In addition, palmitate directly triggers an M1-like macrophage phenotype, and secretions from thus activated macrophages confer insulin resistance to target muscle cells. Together, these studies suggest that in pathophysiological conditions of excess fat, the muscle, endothelial and immune cells engage in a synergistic crosstalk that exacerbates tissue inflammation, leukocyte infiltration, polarization, and consequent insulin resistance.