Fig.2.

Adiponectin signaling pathway regulates intracellular metabolism and neuronal plasticity in (A) physiological- and (B) chronic stress-associated conditions. (A) Activation of the adiponectin receptors, which are present at synapses, orchestrates signaling pathways that are essential for proper bioenergetic balance and plasticity. AdipoR1/2 phosphorylates the APPL1 and activates the AMPK and PPARα pathways, whereas APPL1 itself forms a complex with NMDA receptors and couples neuronal activity with the activation of the insulin signaling pathway (PI3K/Akt). PI3K/Akt induces mTORC1 activity, protein synthesis, and cellular growth by suppressing TSC1/2. Upon synaptic activation, increased AMPK signaling is necessary to upregulate substrate oxidation, mitochondrial respiration and biogenesis, maintaining the intracellular energetic reserves necessary for LTP maintenance. PPARα, on the other hand, directly upregulated CREB transcription. (B) Chronic stress downregulates PPARα and AMPK expression and phosphorylation, as well as downregulates the expression of upstream modulators of the PI3K/Akt pathway, such as vascular endothelial growth factor and insulin. Currently, a direct connection between APPL1 and stress-associated deficits remains unknown.