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Journal of Lipid Research, Vol. 50, 1293-1304, July 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Stephen J. Peterson^3,*,, Dong Hyun Kim^3,*, Ming Li^*, Vincenzo Positano, Luca Vanella^*, Luigi F. Rodella^*, Francesco Piccolomini^*, Nitin Puri^*, Amalia Gastaldelli, Claudia Kusmic, Antonio L'Abbate^,** and Nader G. Abraham^2,*,,

^* Department of Pharmacology, New York Medical College, Valhalla, NY 10595
Department of Medicine, New York Medical College, Valhalla, NY 10595
Central National Research Institute of Clinical Physiology, Pisa, Italy
^** Scuola Superiore Sant'Anna and CNR Institute of Clinical Research, Pisa, Italy
The Rockefeller University, New York 10021
³ S. J. Peterson and D. H. Kim contributed equally to this work.

^* This work was supported by National Institutes of Health Grants DK-068134, HL-55601, and HL-34300 (N.G.A.), by the CNR Medical Department and Cardiopulmonary Project, and by the Scuola Sant'Anna.

¹ This work was presented in part at the American Heart Association, November, 2009.

Published, JLR Papers in Press, March 26, 2009.

² To whom correspondence should be addressed. e-mail: nader_abraham{at}nymc.edu

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.

Supplementary key words diabetes • adiponectin • adiposity • apolipoprotein A-I • heme oxygenase-1 • insulin receptor • insulin sensitivity • obesity • endothelial dysfunction

Abbreviations: FR, fat resonance; HO, heme oxygenase; IOD, integrated optical density; i.p., intraperitoneally; MRS, magnetic resonance spectroscopy; MSC, mesenchymal stem cell; ob, obese; ROS, reactive oxygen species; SAT, subcutaneous fat tissue; SREBP-1, sterol-regulatory element binding protein-1; VAT, visceral fat tissue

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