Apo A1 Mimetic Rescues the Diabetic Phenotype of HO-2 Knockout Mice via an Increase in HO-1 Adiponectin and LKBI Signaling Pathway

Abstract EN

Insulin resistance, with adipose tissue dysfunction, is one of the hallmarks of metabolic syndrome.

We have reported a metabolic syndrome-like phenotype in heme oxygenase (HO)-2 knockout mice, which presented with concurrent HO-1 deficiency and were amenable to rescue by an EET analog.

Apo A-I mimetic peptides, such as L-4F, have been shown to induce HO-1 expression and decrease oxidative stress and adiposity.

In this study we aimed to characterize alleviatory effects of HO-1 induction (if any) on metabolic imbalance observed in HO-2 KO mice.

In this regard, HO-2(−/−) mice were injected with 2 mg/kg/day L-4F, or vehicle, i.p., for 6 weeks.

As before, compared to WT animals, the HO-2 null mice were obese, displayed insulin resistance, and had elevated blood pressure.

These changes were accompanied by enhanced tissue (hepatic) oxidative stress along with attenuation of HO-1 expression and activity and reduced adiponectin, pAMPK, and LKB1 expression.

Treatment with L-4F restored HO-1 expression and activity and increased adiponectin, LKB1, and pAMPK in the HO-2(−/−) mice.

These alterations resulted in a decrease in blood pressure, insulin resistance, blood glucose, and adiposity.

Taken together, our results show that a deficient HO-1 response, in a state with reduced HO-2 basal levels, is accompanied by disruption of metabolic homeostasis which is successfully restored by an HO-1 inducer.