The L-4F mimetic peptide prevents insulin resistance through increased levels of HO-1, pAMPK, and pAKT in obese mice

Stephen J Peterson,Dong Hyun Kim,Ming Li,Vincenzo Positano,Luca Vanella,Luigi F Rodella,Francesco Piccolomini,Nitin Puri,Amalia Gastaldelli,Claudia Kusmic,Antonio L’Abbate,Nader G Abraham

doi:10.1194/jlr.m800610-jlr200

Abstract

We examined mechanisms by which L-4F reduces obesity and diabetes in obese (ob) diabetic mice. We hypothesized that L-4F reduces adiposity via increased pAMPK, pAKT, HO-1, and increased insulin receptor phosphorylation in ob mice. Obese and lean mice were divided into five groups: lean, lean-L-4F-treated, ob, ob-L-4F-treated, and ob-L-4F-LY294002. Food intake, insulin, glucose adipocyte stem cells, pAMPK, pAKT, CB1, and insulin receptor phosphorylation were determined. Subcutaneous (SAT) and visceral adipose tissue (VAT) were determined by MRI and hepatic lipid content by magnetic resonance spectroscopy. SAT and VAT volumes decreased in ob-L-4F-treated animals compared with control. L-4F treatment decreased hepatic lipid content and increased the numbers of small adipocytes (P < 0.05) and phosphorylation of insulin receptors. L-4F decreased CB1 in SAT and VAT and increased pAKT and pAMPK in endothelium. L-4F-mediated improvement in endothelium was prevented by LY294002. Inhibition of pAKT and pAMPK by LY294002 was associated with an increase in glucose levels. Upregulation of HO-1 by L-4F produced adipose remodeling and increased the number of small differentiated adipocytes. The anti-obesity effects of L-4F are manifested by a decrease in visceral fat content with reciprocal increases in adiponectin, pAMPK, pAKT, and phosphorylation of insulin receptors with improved insulin sensitivity.

Highlights

We examined mechanisms by which L-4F reduces obesity and diabetes in obese diabetic mice
MRI and magnetic resonance spectroscopy (MRS) showed that treatment with L-4F resulted in a reciprocal decrease in visceral fat with improvement in vascular dysfunction as determined by the levels of pAMPK, pAKT, and phosphorylation of insulin receptors
L-4F appears capable of reprogramming vascular tissue and adipocytes in a manner that results in the expression of a new phenotype that contains adipocytes of reduced cell size with restored insulin sensitivity

Summary

Introduction

We examined mechanisms by which L-4F reduces obesity and diabetes in obese (ob) diabetic mice. The anti-obesity effects of L-4F are manifested by a decrease in visceral fat content with reciprocal increases in adiponectin, pAMPK, pAKT, and phosphorylation of insulin receptors with improved insulin sensitivity.—Peterson, S. The L-4F mimetic peptide prevents insulin resistance through increased levels of HO-1, pAMPK, and pAKT in obese mice. Recent studies have revealed the presence of myocardial perfusion abnormalities, even in the absence of coronary lesions, in patients with asymptomatic diabetes mellitus [6, 7] This suggests that obesity and diabetes are strongly associated with endothelial dysfunction [8,9,10,11,12,13], increased lipolysis, hepatic triglyceride secretion, and sterol-regulatory element binding protein-1 (SREBP-1) [14].

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Conclusion