The close association of obesity with an increased risk of metabolic diseases, such as insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease, is now well established. In this review, we aim first to describe the inflammatory process activated in response to overnutrition, especially in the liver and the adipose tissue. We then discuss the systemic effects of low-grade inflammation on the onset of insulin resistance. Particular attention is given to a series of very recent reports that identify not only processes but also molecules (lipids and metabolites) that interfere with the normal insulin signaling. Finally, special notes concerning the roles of peroxisome proliferator-activated receptors in the various processes will be made.