Adiponectin-Receptor Agonistic Dipeptide Tyr–Pro Stimulates the Acetylcholine Nervous System in NE-4C Cells

The dipeptide Tyr–Pro has physiological potential for intact transportability into the brain parenchyma, prevention of cognitive impairment, and an adiponectin receptor 1 (AdipoR1) agonistic effect. The present study aimed to understand the effect of Tyr–Pro on the acetylcholine (ACh) nervous system and its underlying mechanism in NE-4C nerve cells. Concentration-dependent ACh production was induced by stimulation with Tyr–Pro and AdipoRon (an AdipoR1 agonist), along with the expression of AdipoR1 and choline acetyltransferase (ChAT) in NE-4C cells. By knocking down AdipoR1 in the cells, Tyr–Pro promoted ChAT expression, along with the activations of AMPK and ERK 1/2. Tyr–Pro did not alter acetylcholinesterase or ACh receptors, indicating that the dipeptide might operate as an ACh accelerator in nerve cells. This study provides the first evidence that the AdipoR1 agonistic Tyr–Pro is a promising dipeptide responsible for the stimulation of the ACh nervous system by AdipoR1-induced ChAT activation.