Figure 3: Downstream signaling cascade of AdipoRs:

Adiponectin binds to the AdipoR, and its binding may be enhanced by T-cadherin. AdipoR signaling targets the cellular metabolic pathways through regulation of mitochondrial biogenesis, lipogenesis and fatty acid oxidation. AdipoR signaling (green) interfaces with insulin receptor signaling (InsR) (orange), which is mediated by sphingosine-1-phosphate receptor (S1PR) and ceramide. High ceramide levels suppress insulin signaling mainly through the inactivation of serine/threonine protein phosphatase 2A (PP2A). By hydrolyzing Ceramide (Cer) to Sphingosine (Sph), AdipoR reduces Cer levels that de-repress PKB via PKCζ. De-repressed PKB inhibits FOXO and thereby downregulates gluconeogenic gene expression. Sph can be phosphorylated to sphingosine-1-phosphate (S1P) that activates S1PR which can induce the downstream mediators of InsR signaling Mapk1 and PKB. S1PR also initiates a PLC mediated IP3 downstream signal that triggers Calcium (Ca²⁺) resulting in activation of AMPK by CAMKK. AMPK spreads the signal across many downstream factors e.g. SirT1, Srebp1 and ACC. AdipoR induces PPARs through a yet to be elucidated pathway. The localization of glucose transporter to the plasma membrane can be impacted by Rab5, AMPK and PKB. The scaffold protein APPL1 binds important signaling mediators and thereby contributes to the crosstalk of AdipoR and InsR as well. ADIPOR also regulates the expression of Cox2 that produces prostaglandin E2 (PGE2).