Molecular mechanisms of signal transduction via adiponectin and adiponectin receptors

The adipocytokine adiponectin and its receptor (AdipoR) comprise a new receptor-ligand system that is involved in a variety of clinically important morbidities such as obesity, type 2 diabetes and cardiovascular diseases. Adiponectin exerts a multitude of beneficial and tissue specific effects depending on its unique, tightly regulated multimerization behavior. Post-translational modifications are essential for the multimer assembly before secretion and protein stability in the circulation. AdipoR1 and 2 have been discovered as a new class of heptahelix receptors structurally and functionally distinct from G-protein-coupled receptors. Both AdipoRs bind adiponectin and the downstream signaling of both AdipoRs is mediated mainly by phosphorylation of AMPK and activation of peroxisome proliferator-activated receptor a, which influence the lipid and glucose metabolism of skeletal muscle and liver cells as well as inflammatory processes and vascular endothelial integrity. Several intracellular binding partners of the AdipoR N-terminus such as APPL1, CK2 beta and ERp46 have been identified and shown to control receptor signaling. Adiponectin has also been reported to modulate the dimerization and internalization of AdipoRs, which provides new insights into the molecular characteristics of this unusual receptor. The understanding of the functional mechanisms of adiponectin signal transduction is critical to benefit from the full therapeutic potential of the adiponectin-AdipoR system.