Dose-dependent effects of central leptin gene therapy on genes that regulate body weight and appetite in the hypothalamus

We have examined the dose-dependent effects and central action of intravent ricular administration of a recombinant adeno-associated virus encoding rat leptin (rAAV-leptin) in suppressing body weight (BW) gain in adult female rats. A low dose of rAAV-leptin (5 x 10(10) particles) suppressed weight ga in (15%) without changing daily food intake (FI), but a twofold higher dose decreased BW by 30% along with a reduction in daily Fl. Reduced BW was due to a loss in body adiposity because serum leptin was reduced. Serum insuli n levels were decreased (96%) by only the high dose along with a slight red uction in glucose. Uncoupling protein-1 (UCP-1) mRNA expression in brown ad ipose tissue (BAT), reflecting energy expenditure through thermogenesis, wa s upregulated to the same magnitude by the two rAAV-leptin doses. We analyz ed by in situ hybridization the expression in the hypothalamus of genes enc oding the appetite-regulating neuropeptides. Only the high dose decreased e xpression of neuropeptide Y (NPY), the orexigenic peptide, and increased pr oopiomelanocortin (POMC), precursor of the anorexigenic peptide, alpha -MSH . Our studies show for the first time that increased availability of leptin within the hypothalamus through central leptin gene therapy dose-dependent ly decreases weight gain, adiposity, and serum insulin by increasing energy expenditure and decreasing Fl. The decrease in F1 occurs only when NPY is reduced and alpha -MSH is increased in the hypothalamus by the high dose of rAAV-leptin. Delivery of the leptin gene centrally through rAAV vectors is a viable therapeutic modality for long-term control of weight and metaboli c hormones.