Abstract Recent goals of swine ration formulation have evolved from preventing nutritional deficiency diseases and maximizing growth performance to optimizing immune function and disease resistance with least climate impact. Thus, certain micronutrients such as selenium (Se) are widely considered to be health beneficial at dietary concentrations above nutrient requirements. During the past decade, we have conducted a number of experiments to determine impacts and mechanisms of dietary Se concentrations (0.03 to 1 or 3 mg/kg) on metabolism of carbohydrate, lipid, and protein in pigs from growing to finishing. Strikingly, pigs fed high-Se diets developed hyperinsulinemia and insulin resistance. Those pigs also had increased lipid, protein, saturated fatty acids (myristic, palmitic, stearic, and behenic acids), and aspartic acid, glutamine, and alanine and decreased polyunsaturated fatty acids (dihomo-γ-linolenic, oleic, α-linolenic, and eicosatrienoic acids) in the liver and(or) adipose tissues. The high-Se diets increased and decreased amounts of 5 and 2 selenoproteins, respectively, in tissues of pigs. These effects were associated with down-regulated insulin signaling (INSR and AKT), glycolysis (glucokinase) and gluconeogenesis (PEPCK) and up-regulated lipogenesis (FOXO1, SREBP1, ACC and FAS), and protein synthesis (mTOR and RPS6/S6). In contrast, high dietary fat intakes up- or down-regulated expressions of all selenoproteins except for TXNRD2 and TXNRD3 and showed a strong effect on expressions of DIO2, GPX6, and SELENOK. These induced selenogenome expression changes were associated with increased serum malondialdehyde and plasma concentrations of tumor necrosis factor alpha and interleukin-6, along with risk of obesity and chronic inflammation. Altogether, metabolisms of micronutrients and macronutrients in pigs are coordinated through interdependent and mutually regulated crossing talks at tissue, cellular, biochemical, and signal levels.