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,Nader G Abraham

doi:10.1194/jlr.m800046-jlr200

Abstract

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-1beta 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-1beta 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.

Highlights

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
Effect of L-4F on bone marrow adiposity and heme oxygenase (HO) activity The adiposity of bone marrow as assessed by the presence of lipid droplets was significantly increased in vehicle-treated obese mice compared with vehicle-treated lean mice (Fig. 6A, B)
L-4F treatment increased the levels of heme oxygenase 1 (HO-1) protein and HO activity to levels significantly greater than those seen in age-matched vehicle-treated lean animals without affecting HO-2 (Fig. 1B)

Summary

Introduction

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 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-1b and IL-6 levels in obese mice. Adipose tissue plays an important role in insulin resistance through the production and secretion of a variety of proteins, including tumor necrosis factor-a (TNF-a,) IL-6, leptin, and adiponectin [10,11,12,13] Of these proteins, adiponectin, which is exclusively secreted from adipose tissue, has insulin-sensitizing properties that enhance fatty acid oxidation, liver insulin action, and glucose uptake and positively affect serum triglyceride levels [12,13,14,15].

Methods

Results

Conclusion