An Explanation for the Adiponectin Paradox

The adipokine adiponectin improves insulin sensitivity. Functional signal transduction of adiponectin requires at least one of the receptors AdipoR1 or AdipoR2, but additionally the glycosyl phosphatidylinositol-anchored molecule, T-cadherin. Overnutrition causes a reduction in adiponectin synthesis and an increase in the circulating levels of the enzyme glycosyl phosphatidylinositol-phospholipase D (GPI-PLD). GPI-PLD promotes the hydrolysis of T-cadherin. The functional consequence of T-cadherin hydrolysis is a reduction in adiponectin sequestration by responsive tissues, an augmentation of adiponectin levels in circulation and a (further) reduction in signal transduction. This process creates the paradoxical situation that adiponectin levels are augmented, whereas the adiponectin signal transduction and insulin sensitivity remain strongly impaired. Although both hypoadiponectinemia and hyperadiponectinemia reflect a situation of insulin resistance, the treatments are likely to be different.