Keeping Obesity and Metabolic Syndrome at Bay with Central Leptin and Cytokine Gene Therapy

Abstract

The incidence of obesity and metabolic syndrome along with the annual cost of treating obesity and related metabolic disorders are rising steeply world wide. In this article, the potential of gene therapy application directly into the hypothalamus, a CNS site involved in integration of energy homeostasis, as a therapeutic modality is reviewed. We engineered a non-immunogenic, non-pathogenic recombinant adeno-associated virus vector to encode leptin, leptin receptor, or the cytokines, leukemia inhibitory factor and ciliary neurotrophic factor. A single injection of virus vectors encoding any of these genes either intraventricularly or into selected hypothalamic sites of wild type or genetically obese rodents curtailed the gradual age-related and rapid high fat diet-induced obesity for long periods. Parameters of metabolic syndrome, hyperleptinemia, hyperinsulinemia and hyperlipidemia were normalized along with fat depletion and increased non-shivering thermogenic energy expenditure either alone or in association with voluntary reduction in food intake. Operation of hypothalamic appetite and energy regulating network was correspondingly modified to conform with the anorectic and obesity suppressing effects of central leptin and cytokine gene therapy. These results advocate central gene therapy as a viable alternative to curb the rising tide of obesity and associated metabolic diseases with or without a voluntary reduction in food intake. Keywords: gene therapy, cytokines, leptin, viral vectors, adeno-associated virus, hypothalamus, adiposity, metabolic syndrome, hyperinsulinemia, type 2 diabetes