Insulin resistance is a major feature of obesity and a key factor in the development of type 2 diabetes. This review discusses the mechanisms by which nutrient excess and obesity lead to insulin resistance, highlighting the interplay between nutrient sensing pathways, inflammation, and insulin signaling. Obesity leads to insulin resistance through systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation, with macrophages playing a central role in propagating inflammation and inducing insulin resistance. Insulin resistance is characterized by impaired glucose uptake in skeletal muscle, reduced inhibition of hepatic glucose production, and decreased inhibition of lipolysis in adipose tissue. It is a major predictor of metabolic diseases, including type 2 diabetes and the metabolic syndrome. Insulin resistance can be genetic or acquired, with environmental factors such as obesity, sedentary lifestyle, and aging playing a significant role. In type 2 diabetes, insulin resistance precedes overt hyperglycemia. Nutrient availability and pathways that sense nutrients are critical in modulating insulin signaling. Nutrient availability and obesity interact to modulate inflammatory pathways in liver and adipose tissue, with macrophages playing a key role in this process. Other factors, such as the CNS and genetics, also influence obesity, insulin sensitivity, and type 2 diabetes. In skeletal muscle and adipose tissue, insulin promotes glucose uptake by activating a complex signaling cascade. In adipose tissue, insulin inhibits fatty acid release. Insulin resistance can be caused by the phosphorylation of serine residues on IRS-1, which impairs insulin signaling. This process is linked to proinflammatory pathways, including JNK and IKK. Nutrient availability and acute changes in energy balance can rapidly modulate insulin sensitivity, as seen in studies of calorie restriction and gastric bypass surgery. Fatty acid flux is a key mediator of insulin resistance in obesity. Increased fatty acid flux leads to the accumulation of fatty acid intermediates, which activate serine kinases and impair insulin action. Fatty acid metabolism in skeletal muscle and liver can regulate insulin action through pathways such as mTOR/p70S6K, JNK, IKK, and PKC. SIRT1 is a positive regulator of insulin sensitivity. Chronic modulation of insulin sensitivity in obesity involves increased fatty acid flux, nutrient overload, microhypoxia, ER stress, and chronic tissue inflammation. Inflammation is a key link between obesity and insulin resistance. Adipose tissue, which is not only a storage depot but also an active secretor of cytokines and adipokines, plays a central role in this process. Adipose tissue microhypoxia and ER stress activate inflammatory pathways, leading to the recruitment of proinflammatory macrophages. These macrophages release cytokines that activate inflammatory pathways in neighboring cells, leading to cell autonomous insulin resistance. Macrophage heterogeneity and polarization, with M1 and M2 macrophages playing distinct roles, are importantInsulin resistance is a major feature of obesity and a key factor in the development of type 2 diabetes. This review discusses the mechanisms by which nutrient excess and obesity lead to insulin resistance, highlighting the interplay between nutrient sensing pathways, inflammation, and insulin signaling. Obesity leads to insulin resistance through systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation, with macrophages playing a central role in propagating inflammation and inducing insulin resistance. Insulin resistance is characterized by impaired glucose uptake in skeletal muscle, reduced inhibition of hepatic glucose production, and decreased inhibition of lipolysis in adipose tissue. It is a major predictor of metabolic diseases, including type 2 diabetes and the metabolic syndrome. Insulin resistance can be genetic or acquired, with environmental factors such as obesity, sedentary lifestyle, and aging playing a significant role. In type 2 diabetes, insulin resistance precedes overt hyperglycemia. Nutrient availability and pathways that sense nutrients are critical in modulating insulin signaling. Nutrient availability and obesity interact to modulate inflammatory pathways in liver and adipose tissue, with macrophages playing a key role in this process. Other factors, such as the CNS and genetics, also influence obesity, insulin sensitivity, and type 2 diabetes. In skeletal muscle and adipose tissue, insulin promotes glucose uptake by activating a complex signaling cascade. In adipose tissue, insulin inhibits fatty acid release. Insulin resistance can be caused by the phosphorylation of serine residues on IRS-1, which impairs insulin signaling. This process is linked to proinflammatory pathways, including JNK and IKK. Nutrient availability and acute changes in energy balance can rapidly modulate insulin sensitivity, as seen in studies of calorie restriction and gastric bypass surgery. Fatty acid flux is a key mediator of insulin resistance in obesity. Increased fatty acid flux leads to the accumulation of fatty acid intermediates, which activate serine kinases and impair insulin action. Fatty acid metabolism in skeletal muscle and liver can regulate insulin action through pathways such as mTOR/p70S6K, JNK, IKK, and PKC. SIRT1 is a positive regulator of insulin sensitivity. Chronic modulation of insulin sensitivity in obesity involves increased fatty acid flux, nutrient overload, microhypoxia, ER stress, and chronic tissue inflammation. Inflammation is a key link between obesity and insulin resistance. Adipose tissue, which is not only a storage depot but also an active secretor of cytokines and adipokines, plays a central role in this process. Adipose tissue microhypoxia and ER stress activate inflammatory pathways, leading to the recruitment of proinflammatory macrophages. These macrophages release cytokines that activate inflammatory pathways in neighboring cells, leading to cell autonomous insulin resistance. Macrophage heterogeneity and polarization, with M1 and M2 macrophages playing distinct roles, are important