This review by Schenk, Saberi, and Olefsky discusses the mechanisms by which nutrient excess and obesity lead to insulin resistance. They highlight the role of nutrient sensors in skeletal muscle and liver, which can regulate insulin action. The authors also explore how obesity causes insulin resistance through a complex interplay involving systemic fatty acid excess, microhypoxia in adipose tissue, endoplasmic reticulum (ER) stress, and inflammation. A particular focus is placed on the role of macrophages in propagating inflammation and inducing insulin resistance. The review provides an integrative perspective on how nutrients and obesity interact to regulate insulin sensitivity, emphasizing the importance of inflammatory pathways and nutrient sensors in this process. The authors conclude by discussing the acute and chronic modulation of insulin sensitivity, the role of fatty acid metabolism, and the involvement of macrophages in the propagation of inflammation and insulin resistance.This review by Schenk, Saberi, and Olefsky discusses the mechanisms by which nutrient excess and obesity lead to insulin resistance. They highlight the role of nutrient sensors in skeletal muscle and liver, which can regulate insulin action. The authors also explore how obesity causes insulin resistance through a complex interplay involving systemic fatty acid excess, microhypoxia in adipose tissue, endoplasmic reticulum (ER) stress, and inflammation. A particular focus is placed on the role of macrophages in propagating inflammation and inducing insulin resistance. The review provides an integrative perspective on how nutrients and obesity interact to regulate insulin sensitivity, emphasizing the importance of inflammatory pathways and nutrient sensors in this process. The authors conclude by discussing the acute and chronic modulation of insulin sensitivity, the role of fatty acid metabolism, and the involvement of macrophages in the propagation of inflammation and insulin resistance.