We show here that dietary intake of kaempferol for 5 months (mo) improved insulin sensitivity and glucose tolerances, which were associated with increased Glut4 and AMPKα expression in muscle and adipose tissues in middle-aged mice fed a high-fat (HF) diet. In vitro, kaempferol increased lipolysis and restored chronic high fatty acid-impaired glucose uptake and glycogen synthesis in skeletal muscle cells, which were associated with improved AMPKα activity and Glut4 expression. The gene discussed is INS; the disease is hydrops fetalis.