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Journal of Lipid Research, Vol. 49, 1658-1669, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin sensitivity in obese mice^*

Stephen J. Peterson^*, George Drummond, Dong Hyun Kim, Ming Li, Adam L. Kruger^*, Susumu Ikehara and Nader G. Abraham^1,*,

^* Departments of Medicine New York Medical College, Valhalla, NY 10595
Department of Pharmacology, New York Medical College, Valhalla, NY 10595
First Department of Pathology, Kansai Medical University, Moriguchi, Osaka, Japan

^* This work was supported by National Institutes of Health Grants DK-068134, HL-55601, and HL-34300.

Published, JLR Papers in Press, April 28, 2008.

¹To whom correspondence should be addressed. e-mail: nader_abraham{at}nymc.edu

We hypothesized that the apolipoprotein mimetic peptide L-4F, which induces arterial anti-oxidative enzymes and is vasoprotective in a rat model of diabetes, would ameliorate insulin resistance and diabetes in obese mice. L-4F (2 mg/kg/d) administered to ob/ob mice for 6 weeks limited weight gain without altering food intake, decreased visceral (P < 0.02) and subcutaneous (P < 0.045) fat content, decreased plasma IL-1β and IL-6 levels (P < 0.05) and increased insulin sensitivity, resulting in decreased glucose (P < 0.001) and insulin (P < 0.036) levels. In addition, L-4F treatment increased aortic and bone marrow heme oxygenase (HO) activity and decreased aortic and bone marrow superoxide production (P < 0.001). L-4F treatment increased serum adiponectin levels (P < 0.037) and decreased adipogenesis in mouse bone marrow (P < 0.039) and in cultures of human bone marrow-derived mesenchymal stem cells (P < 0.022). This was manifested by reduced adiposity, improved insulin sensitivity, improved glucose tolerance, increased plasma adiponectin levels, and reduced IL-1β and IL-6 levels in obese mice. This study highlights the existence of a temporal relationship between HO-1 and adiponectin that is positively affected by L-4F in the ob/ob mouse model of diabetes, resulting in the amelioration of the deleterious effects of diabetes.

Supplementary key words diabetes • apolipoprotein A-I mimetic peptides • heme oxygenase-1

Abbreviations: apoA-I, apolipoprotein A-I; HMW, high molecular weight; HO, heme oxygenase; LMW, low molecular weight; MSC, mesenchymal stem cell; ROS, reactive oxygen species

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