fADN interacts with AdipoR2 on the syncytial plasma membrane. Mediated by interaction with APPLs, this results in the activation of p38 MAPK and PPARα. Activation of PPARα dependent gene transcription leads to changes in sphingolipid metabolizing enzymes promoting ceramide biosynthesis. Consequently, elevated intracellular ceramide impairs IRS-1 activity and its downstream signaling of Akt and mTORC1, thereby inhibiting amino acid transport. Solid lines represent previously established processes, dashed lines indicate hypothetical mechanisms. AAT, amino acid transporters; 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; IR, insulin receptor; IRS-1, insulin receptor substrate-1; mTORC1, mammalian target of rapamycin complex 1; p38 MAPK, p38 mitogen-activated protein kinase; PPARα, peroxisome proliferator-activated receptor alpha; SPL, sphingolipid.