Background and Aim: Apolipoprotein-AI (apo-AI) is the major apolipoprotein found in high density lipoprotein particles (HDLs). Recently, we have shown that full-length apoAI injected into a mouse model of insulin resistance, the high fat diet (HFD)-fed C57BL/6 mouse, improved insulin sensitivity. While our recent data provides compelling proof of concept data, intact apoA-I is not suitable as a therapy option due to the time and cost associated with its production and administration. The aim of the present study was to test whether apoA-I mimetic peptide treatment will emulate the effects of full-length apoAI to improve insulin resistance.
Method and Results: Insulin resistant C57BL/6 mice were generated by 16-weeks of HFD. Mice treated with apo A-I mimetic 5F peptide synthesized from L-amino acids (L-5F; administered by twice weekly intraperitoneal injections) or treated with apoA-I mimetic peptide 4-F synthesized from D-amino acids (D-4F; administered via drinking water) showed: (i) improved glucose tolerance and insulin sensitivity that was associated with decreased hepatic inflammation (TNFalpha, IL6, IL-1beta and IFN-gamma); (ii) suppression of hepatic mRNA expression of gluconeogenesis-associated genes (PEPCK and G6Pase) and lipogenic-associated genes (SREBP1c and ChREBP) and; (iii) reduced hepatic macrophage infiltration.
Conclusions: We conclude that both the apoA-I mimetic peptides, L5-F and D4-F, improve insulin sensitivity in HFD-fed C57BL/6 mice. This effect is associated with reduced expression of inflammatory markers in the liver, reduced infiltration of macrophages and altered gene expression of genes associated with gluconeogenesis and lipid synthesis suggesting that glucose and lipid synthesis is suppressed. Together, these findings suggest that apoA-I mimetic peptides could be considered as a new therapeutic option to reduce hepatic inflammation that contributes to the development of overnutrition-induced insulin resistance.