Abstract 19492: Adipose-Specific Gene Therapy Corrects Leptin Deficiency in vivo
Objective: To develop an in vivo, systemic method of gene therapy specifically targeting adipose tissue. We assessed the hypothesis that adipose-specific gene therapy using adeno-associated viruses (AAV) can correct leptin deficiency in vivo.
Background: Obesity is a major risk factor for developing coronary heart disease. Adipose is an endocrine organ critical for energy intake and expenditure. Available data on adipose is limited, in part, because of the difficulties in adapting experimental techniques to tissue with high lipid content. Few studies have investigated in vivo gene transfer in adipose tissue, and these studies used subcutaneous injections in obese mice.
Method and Results: Tail vein iv delivery of genes to adipose tissue was assessed in healthy C57BL/6 mice injected with AAV serotype 8 (AAV8) containing the expression vector of interest. Mice were sacrificed 2-3 weeks after injection, and tissues were analyzed for transgene expression. Systemic delivery of a vector containing the GFP gene under control of a CMV promoter induced GFP transgene expression in most tissues, including all adipose depots tested. Replacing the CMV promoter with an adiponectin enhancer/promoter unit and incorporating liver specific micro-RNA-122 target sites into the vector restricted GFP expression to adipose tissue. The leptin gene was put into the adipose-targeted expression vector and delivered by AAV8 to 9-10 week old ob/ob mice. Phenotypic changes were then measured for 8 weeks. Expression of leptin gene was detectable in multiple adipose tissue beds at both RNA and protein levels in mice receiving AAV8 leptin vector, but absent in control mice. Mice receiving leptin gene ate less food and had lower insulin levels compared to control mice. At sacrifice, average weight of mice receiving leptin gene was 14 g less than control mice. Glucose tolerance tests demonstrated adipose-targeted leptin gene therapy increased insulin sensitivity in ob/ob mice.
Conclusion: AAV8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and thus correct for leptin deficiency in ob/ob mice. This novel approach has therapeutic potential in obesity and downstream complications such as insulin resistance and diabetes.
- © 2012 by American Heart Association, Inc.