Adiponectin is an adipokine produced primarily by adipose tissue, which plays a crucial role in insulin sensitivity and metabolic homeostasis. Hypoadiponectinemia, caused by genetic and environmental factors, is associated with insulin resistance, type 2 diabetes, and the metabolic syndrome. The adiponectin receptors, AdipoR1 and AdipoR2, mediate the antidiabetic and metabolic actions of adiponectin, and their downregulation is observed in obesity-linked insulin resistance. Thiazolidinediones (TZDs) increase adiponectin levels and improve insulin sensitivity by activating PPARγ, which also upregulates adiponectin receptors. The high molecular weight (HMW) form of adiponectin is more active and correlates better with insulin sensitivity and metabolic parameters. The adiponectin hypothesis suggests that reduced plasma adiponectin levels, influenced by genetic and environmental factors, contribute to the development of insulin resistance and related metabolic disorders. Therapeutic strategies targeting adiponectin or its receptors may offer novel approaches to treating these conditions.Adiponectin is an adipokine produced primarily by adipose tissue, which plays a crucial role in insulin sensitivity and metabolic homeostasis. Hypoadiponectinemia, caused by genetic and environmental factors, is associated with insulin resistance, type 2 diabetes, and the metabolic syndrome. The adiponectin receptors, AdipoR1 and AdipoR2, mediate the antidiabetic and metabolic actions of adiponectin, and their downregulation is observed in obesity-linked insulin resistance. Thiazolidinediones (TZDs) increase adiponectin levels and improve insulin sensitivity by activating PPARγ, which also upregulates adiponectin receptors. The high molecular weight (HMW) form of adiponectin is more active and correlates better with insulin sensitivity and metabolic parameters. The adiponectin hypothesis suggests that reduced plasma adiponectin levels, influenced by genetic and environmental factors, contribute to the development of insulin resistance and related metabolic disorders. Therapeutic strategies targeting adiponectin or its receptors may offer novel approaches to treating these conditions.