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

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.

Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer

“…The values shown are the Mean ± SD. *P < 0.05. tein mimetic peptides in models of inflammatory disorders other than atherosclerosis suggest that they have efficacy in a wide range of inflammatory conditions (10, 13), including, in animal models of dyslipidemia (10,11,42,43), diabetes and vascular inflammation (44)(45)(46)(47)(48), renal disease (12,49), sepsis (50), and Alzheimer's disease (51). Our studies demonstrate that apoA-I mimetic peptides are very effective in preventing the development of tumors (Figs.…”

ApoA1

“…Adipocyte enlargement is associated with an increase in the release of TNFα, IL-1, IL-6 and increased insulin resistance. [6][7][8]25 Induction of HO-1 has been shown to enhance cell survival and moderate the diabetic state and obesity. [37][38][39] Induction of HO-1 gene expression in vivo and in cell culture is associated with an increase in pre-adipocytes, a reduction in the number of enlarged adipocytes, but an increase in small adipocyte and adiponectin levels.…”

“…Insulin resistance, a result of high fat intake and inactivity leading to obesity, is a cause of vascular dysfunction. [1][2][3][4][5] Increasing adipocyte size has been shown in individuals with adult-onset obesity, where adipocyte hypertrophy and hyperplasia has been reported in rodents [6][7][8] and in individuals with early-onset obesity. 9 Adipocyte size increase results from either the increased storage of triglycerides from dietary sources or is generated by lipogenic pathways; new adipocytes may arise via the proliferation and differentiation of both pre-adipocytes and adipoblasts to mature adipocytes.…”

HDLs, Diabetes, and Metabolic Syndrome

“…This was associated with increased energy expenditure as measured in metabolic cages and related to increased expression of uncoupling protein 1 (UCP-1) in brown adipose tissue and AMPK phosphorylation (Ruan et al 2011). Consistent with these results is the observation that administration of D-4F and L-4F in high-fat diet-fed mice reduced weight gain and improved insulin sensitivity when compared with age-matched vehicle-treated mice (Peterson et al 2009). Taken together, these observations implicate a potential antiobesity effect of ApoA-I.…”