Activation of insulin signaling and energy sensing network by AICAR, an AMPK activator in insulin resistant rat tissues.

Background: The energy status of the cell is regulated by the energy sensing network constituted by AMP-activated protein kinase (AMPK), the NAD+-dependent type III deacetylase silence information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). This study investigates the potential effect of 5-aminoimidazole-4-carboximide-1-b-D-ribofuranoside (AICAR), an AMPK activator on insulin signaling and energy sensing network in insulin resistant rats.

Methods: Adult male albino Wistar rats with body weight of 150-180 g were fed high-fructose diet (HFD) for 60 days to induce insulin resistance. Rats fed HFD were divided into two and were treated or untreated with AICAR (0.7 mg/kg bw, i.p.) for the last 2 weeks.

Results: Insulin resistant rats displayed increased glucose and insulin levels and reduced tyrosine phosphorylation of insulin resistance receptor and insulin receptor substrate 1. The downstream signaling and glucose transport were also affected. Phosphorylation of AMPK, SIRT1 protein abundance and mRNA expression of PGC-1α were reduced. Treatment with AICAR reduced hyperglycemia and hyperinsulinemia and improved the activation of the key molecules of insulin signaling. Improved action of energy sensing network was noted after AICAR treatment. AICAR showed higher binding affinity with Akt (-8.2 kcal/mol) than with AMPK or insulin receptor (-8.0 kcal/mol) in the in silico study.

Conclusions: The findings suggest that AICAR, the AMPK activator, influences insulin signaling proteins and molecules involved in energy modulation during insulin resistance.