title: Heme oxygenase gene targeting to adipocytes attenuates adiposity and vascular dysfunction in mice fed a high-fat diet.
abstract: We examined the hypothesis that adipocyte dysfunction in mice fed a high-fat (HF) diet can be prevented by lentiviral-mediated and adipocyte specific-targeting delivery of the human heme oxygenase-1 (aP2-HO-1). A bolus intracardial injection of aP2-HO-1 resulted in expression of human HO-1 for up to 9.5 months. Transduction of aP2-HO-1 increased human HO-1 expression in fat tissues without affecting murine HO-1. In mice fed a HF diet, aP2-HO-1 transduction attenuated the increases in body weight, blood glucose, blood pressure, and inflammatory cytokines, as well as the content of both visceral and subcutaneous fat. Transduction of aP2-HO-1 increased the numbers of adipocytes of small cell size (P<0.05), insulin sensitivity (P<0.05), adiponectin levels, as well as vascular relaxation to acetylcholine compared with HF mice administered the aP2-green fluorescent protein. Adipocytes of mice fed a HF diet expressed high levels of peroxisome proliferator activator receptor, aP2, C/EBP, and Wnt5b proteins and displayed marked increases in Peg1/Mesoderm specific transcript (P<0.03). Transduction of aP2-HO-1 lowered the elevated levels of these proteins and increased Sonic hedgehog, Wnt10b, and β-catenin (P<0.05). Inhibition of HO activity by administration of tin mesoporphyrin to HF-fed mice transduced with the aP2-HO-1 reversed the decrease in Peg1/Mesoderm-specific transcript, TNFα, and MCP-1 levels. Collectively, this novel study demonstrates 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 by decreasing inflammatory cytokines. These effects are reversed by the HO activity inhibitor, stannous mesoporphyrin.
authors: Department of Geriatric Cardiology, Chinese PLA General Hospital Beijing, China.
authors: Jian
authors: J
authors: Cao
authors: Stephen J
authors: SJ
authors: Peterson
authors: Komal
authors: K
authors: Sodhi
authors: Luca
authors: L
authors: Vanella
authors: Ignazio
authors: I
authors: Barbagallo
authors: Luigi F
authors: LF
authors: Rodella
authors: Michal L
authors: ML
authors: Schwartzman
authors: Nader G
authors: NG
authors: Abraham
authors: Attallah
authors: A
authors: Kappas
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050154:Adiposity / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000503:physiopathology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008665:Metalloporphyrins; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; C468567:Wnt5b protein, mouse; D051176:beta Catenin; C103637:mesoderm specific transcript protein; C518404:stannous mesoporphyrin; D051547:Heme Oxygenase-1