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

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-1b 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-1b 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.-Peterson,

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…This hypothesis is corroborated by the ability of HDL to reduce the expression of hormone-sensitive lipase (Van Linthout et al 2010a), the rate-limiting enzyme of adipocyte lipolysis in abdominal fat (Sztalryd and Kraemer 1995), and to increase the phosphorylation of the PI3K downstream target Akt in abdominal fat (Van Linthout et al 2010a). Akt is involved in the anti-lipolytic and lipogenic effects of insulin in adipose tissue (Whiteman et al 2002) and in the regulation of the expression of the adipokine adiponectin (Cong et al 2007;Pereira and Draznin 2005), which is known to improve insulin sensitivity under diabetes (Peterson et al 2008). However, an involvement of HDL in the hepatic expression of genes involved in triglyceride metabolism may not be excluded.…”

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

“…In an in vivo study, apoA-I infusion in rabbits in acute vascular inflammation model reduced neutrophil infiltration and endothelial cell inflammatory activation (Puranik et al 2008). In addition, apoA-1 mimetic peptides have been shown to reduce vascular inflammation in type I diabetic rats and improve insulin sensitivity in obese mice (Peterson et al 2007(Peterson et al , 2008. It has also been demonstrated that treatment with lipid-free apoA-I and rHDL treatment reduced the expression of chemokines and chemokine receptors in vitro and in vivo by modulating NF-κB and peroxisome proliferator-activated receptor γ (Bursill et al 2010).…”

Treatment of Obese Diabetic Mice With a Heme Oxygenase Inducer Reduces Visceral and Subcutaneous Adiposity, Increases Adiponectin Levels, and Improves Insulin Sensitivity and Glucose Tolerance

“…Recently, L'Abbate et al (24) have shown that induction of HO-1 was associated with a parallel increase in the serum levels of adiponectin, which has well-documented anti-inflammatory properties (24). Adiponectin has been ascribed antioxidative properties (25,26). These observations also serve to define some of the key mechanisms by which HO-1 is involved in diabetes and the metabolic syndrome.…”

“…Specimens were maintained at Ϫ80°C until needed. Frozen aorta and kidney segments were pulverized, and the supernatant was isolated and used for HO activity, HO-1 and HO-2 protein (26). HO activity assay and CO generation.…”