Role of Perivascular Adipose Tissue-Derived Adiponectin in Vascular Homeostasis

Figure 1. Mechanism of adiponectin-dependent AMPK activation. (A) In the non-stimulated state, APPL1 and protein phosphatase 2A (PP2A) do not interact. Protein kinase Cζ (PKCζ) phosphorylates liver kinase B 1 (LKB1) and induces its translocation to the nucleus. (B) Upon adiponectin (APN) binding, PKCζ is dephosphorylated by PP2A. Dephosphorylated PKCζ is no longer able to phosphorylate LKB1. PP2A also dephosphorylates LKB1, which results in LKB1 translocation to the cytoplasm. LKB1 phosphorylates AMP-activated protein kinase (AMPK) in the form of the AdipoR1/APPL1/PP2A/ PKCζ/LKB1 complex.

Figure 2. Mechanism of adiponectin-dependent MAPK activation. (A) In the non-stimulated state, adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif (APPL1) weakly interacts with transforming growth factor-β-activated kinase 1 (TAK1). (B) Upon adiponectin (APN) binding to the adiponectin receptor 1 (AdipoR1), APPL1 and phosphorylated TAK1 are recruited to the receptor site. This triggers the recruitment of two further proteins: p38 mitogen-activated protein kinase (p38 MAPK) and mitogen-activated protein kinase kinase 3 (MKK3). (C) TAK1 phosphorylates MKK3 and dissociates from the complex. MKK3 phosphorylates p38 MAPK, and both proteins dissociate from the complex. Phosphorylated p38 MAPK subsequently induces fatty acid oxidation and glucose uptake.

Figure 3. Integration of insulin and adiponectin signaling pathways. (A) Upon adiponectin or insulin stimulation, PKC phosphorylates APPL1. This results in insulin receptor 1/2 (IRS1/2) and Akt recruitment, resulting in APPL1/IRS1/2/Akt complex formation. This complex then associates with the insulin receptor (IR). (B) After the binding of insulin (INS) to the IR, APPL1 “piggybacks” Akt and IRS1/2 on the IR. (C) Dephosphorylated APPL1 dissociates from the complex. (D) IRS1/2 phosphorylates phosphatidylinositol-3 kinase (PI3K), and PI3K phosphorylates Akt, which activates its further substrates in the insulin signaling pathway.