Adiponectin-signaling is mediated via AdipoR1 and AdipoR2. AdipoR1 binds gADN with high affinity and fADN with low affinity, whereas AdipoR2 binds both gADN and fADN with intermediate affinity. Adaptor protein APPL1 interacts with adiponectin receptors and mediates the activation of downstream targets, while APPL2 is bound to APPL1 in the receptor inactive state and inhibits signaling activity. AdipoR1/2, adiponectin receptor 1/2; APPL1/2, adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif 1/2; fADN, full-length adiponectin; gADN, globular adiponectin; Int, intermediate.