Abstract
Obesity and associated metabolic comorbidities represent a growing public health problem. In this study, we demonstrate the use of a newly created fusion gene of exendin-4 and α1-antitrypsin to control obesity and obesity-associated metabolic disorders including insulin resistance, fatty liver and hyperglycemia. The fusion gene encodes a protein with exendin-4 peptide placed at the N-terminus of human α-1 antitrypsin, and is named EAT. Hydrodynamic transfer of the EAT gene to mice prevents high-fat diet-induced obesity, insulin resistance and fatty liver development. In diet-induced obese mice, expression of EAT gene induces weight loss, improves glucose homeostasis, and attenuates hepatic steatosis. In ob/ob mice, EAT gene transfer suppresses body weight gain, maintains metabolic homeostasis, and completely blocks fatty liver development. Six-month overexpression of the EAT fusion gene in healthy mice does not lead to any detectable toxicity. Mechanistic study reveals that the resulting metabolic benefits are achieved by a reduced food take and down-regulation of transcription of pivotal genes responsible for lipogenesis and lipid droplet formation in the liver and chronic inflammation in visceral fat. These results validate the feasibility of gene therapy in preventing and restoring metabolic homeostasis under diverse pathologic conditions, and provide evidence in support of a new strategy to control obesity and related metabolic diseases.