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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 ?-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, TNF?, 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.

SUBMITTER: Cao J

PROVIDER: S-EPMC3423899 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other

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Heme oxygenase gene targeting to adipocytes attenuates adiposity and vascular dysfunction in mice fed a high-fat diet.

Cao Jian J Peterson Stephen J SJ Sodhi Komal K Vanella Luca L Barbagallo Ignazio I Rodella Luigi F LF Schwartzman Michal L ML Abraham Nader G NG Kappas Attallah A

Hypertension (Dallas, Tex. : 1979) 20120702 2

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 ...[more]

PMID: 22753217

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Project description:Pharmacological agents that block beta-adrenergic receptors have been associated with improved outcome in burn injury. It has been hypothesized that injuries leading to a hypermetabolic state, such as septic shock, may also benefit from beta-blockade; however, outcome data in experimental models have been contradictory. Thus, we investigated the effect of beta-blockade with propranolol on survival, hemodynamics, lung heat shock protein (HSP) expression, metabolism and inflammatory markers in a rat cecal ligation and puncture (CLP) model of sepsis.Sprague-Dawley rats receiving either repeated doses (30 minutes pre-CLP and every 8 hours for 24 hours postoperatively) of propranolol or control (normal saline), underwent CLP and were monitored for survival. Additionally, lung and blood samples were collected at 6 and 24 hours for analysis. Animals also underwent monitoring to evaluate global hemodynamics.Seven days following CLP, propranolol improved survival versus control (P < 0.01). Heart rates in the propranolol-treated rats were approximately 23% lower than control rats (P < 0.05) over the first 24 hours, but the mean arterial blood pressure was not different between groups. Metabolic analysis of lung tissue demonstrated an increase in lung ATP/ADP ratio and NAD+ content and a decreased ratio of polyunsaturated fatty acids to monounsaturated fatty acids (PUFA/MUFA). Cytokine analysis of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) demonstrated decreased expression of TNF-alpha in both lung and plasma at 24 hours post CLP induced sepsis. Finally, propranolol led to a significant increase in lung hemeoxygenase-1 expression, a key cellular protective heat shock protein (HSP) in the lung. Other lung HSP expression was unchanged.These results suggest that propranolol treatment may decrease mortality during sepsis potentially via a combination of improving metabolism, suppressing aspects of the inflammatory response and enhancing tissue protection.

Dataset Information

Heme oxygenase gene targeting to adipocytes attenuates adiposity and vascular dysfunction in mice fed a high-fat diet.

Publications

Heme oxygenase gene targeting to adipocytes attenuates adiposity and vascular dysfunction in mice fed a high-fat diet.

Similar Datasets

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