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.
Highlights
This difficulty stems primarily from the complex pathophysiology of obesity which includes excess food intake and chronic inflammation[6,7,8]
To verify whether the functions of human α-1 antitrypsin (hAAT) and Ex4 are preserved in fusion protein, pEAT plasmids were transfected into HEK293T cells using branched polyethylenimine (PEI) as a transfection reagent and EAT recombinant proteins were purified using Ni-NTA affinity chromatography
Florescence-based proteinase assay shows that purified EAT protein has comparable activity to that of pure hAAT protein in inhibiting elastase activity (Fig. 1C), while native Ex4 peptide showed no activity at equal molar level (Fig. 1D)
Summary
This difficulty stems primarily from the complex pathophysiology of obesity which includes excess food intake and chronic inflammation[6,7,8]. Reduction in GLP-1 release has been shown in obese patients, resulting in excess energy intake and imbalance of metabolic homeostasis[9,10,11]. In addition to excess energy intake, another typical feature of morbid obesity is chronic inflammation which plays an indispensable role in the initiation and progression of obesity-related metabolic complications[7,12,13]. Simultaneous repressing energy intake and relieving inflammation is expected to reduce body weight, promote adipose remodeling, and lead to restoration of metabolic homeostasis. We provide evidence in support of the feasibility of a gene therapy-based strategy to manage obesity and obesity-associated metabolic disorders
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