Abstract 61: Adipose Tissue Specific HO-1 Induction Regulates the Crosstalk between Wnt and β-catenin Pathways and Leads to Restoration of Vascular Endothelial Function in Mice Fed a High Fat Diet

Abstract

The principal goal of the present study is to examine the contributions of adipocyte specific over expression of the cytoprotective gene heme oxygenase-1 (HO-1) in modulating vascular function in an animal model of diet induced obesity. A lentiviral construct of the human HO-1 was synthesized under the control of an aP2-activated promoter so as to ensure HO-1 targeting to murine adipocytes. Lentiviruses (50 μl, 2x109 TU/ml in saline) were injected into the C57BL/6 mice by a single intracardiac injection. Mice (6-7 wks old) were divided into 4 groups: Control, high fat diet (HF) mice receiving the control Lenti-aP2-GFP (HF-GFP) and high fat diet mice receiving the lenti-aP2-HO-1 (HF-HO-1) with and without treatment with SnMP. Transduction of lenti-aP2-HO-1 increased human HO-1 expression in adipose tissues without affecting endogenous mice HO-1 (p<0.01). In mice fed a HF diet, lenti-aP2-HO-1 transduction attenuated the increases in body weight (from 52.0±1.0 g to 35.6±2.1g; p<0.01), blood glucose (from 255±3.5 g to 140±2.9mg/dl), blood pressure (from 135±2.8mmHg to 101±2.2mmHg; p<0.01) and inflammatory cytokines as well as the content of both visceral (from 5.5±0.15g to 2.9±0.22g; p<0.05) and subcutaneous fat (p<0.05). Transduction of lenti-aP2-HO-1 increased the numbers of adipocytes of small cell size (p<0.05), insulin sensitivity (p<0.05), adiponectin levels (from 32.4±1.9μg/ml to 19.9±2.1μg/ml; p<0.05) as well as vascular relaxation to acetylcholine ( p<0.05) compared to HF mice administered the lenti-aP2- GFP. Adipocytes of mice fed a HF diet expressed high levels of PPARγ, aP2, C/EBP and Wnt5b proteins and displayed marked increases in Peg1/Mest (p<0.03). Lenti-aP2-HO-1 transduction lowered the elevated levels of these proteins and increased Shh, Wnt10b and β-catenin (p<0.05). Inhibition of HO activity by administration of tin mesoporphyrin (SnMP) to HF-fed mice transduced with the lenti-aP2-HO-1 reversed the decrease in Peg 1/Mest, TNFα and MCP-1 levels. This novel study demonstrate that adipocyte-specific overexpression of HO-1 attenuates HF-mediated adiposity and vascular dysfunction, increases insulin sensitivity and improves adipocyte function by increasing adiponectin, Shh and WNT10b and decreasing inflammatory cytokines.