Hydrodynamic delivery of FGF21 gene alleviates obesity and fatty liver in mice fed a high-fat diet

Apr 22, 2014Journal of controlled release : official journal of the Controlled Release Society

Delivering the FGF21 gene to reduce obesity and fatty liver in mice on a high-fat diet

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Abstract

Transfer of the FGF21 gene resulted in a peak blood protein level of 500 ng/ml within 1 day.

FGF21 gene transfer increased mRNA levels of FGF21 exclusively in the liver.
This gene transfer blocked high fat diet-induced obesity and improved glucose regulation.
Altered expression of genes related to thermogenesis, fat storage, and inflammation was observed.
Increased expression of thermogenic genes in adipose tissue was linked to reduced fat mass and less insulin resistance.
Lean mice receiving FGF21 showed decreased fat production in the liver and improved glucose tolerance.

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FGF21 is a secreted protein that plays critical roles in regulating glucose and lipid metabolism. In this study, we evaluated the effects of FGF21 gene transfer on C57BL/6 mice fed a high fat diet (HFD). We demonstrate that transfer of the FGF21 gene using a hydrodynamics-based procedure increased mRNA levels of FGF21 exclusively in the liver, consequently generating a sustained high level of FGF21 protein in blood that peaked at 500 ng/ml 1 day after injection, leading to a variety of beneficial effects including blockade of HFD-induced obesity, alleviation of fatty liver and improvement in glucose homeostasis. These effects were associated with altered expression of Ucp1, Dio2, Pgc1α, Pparγ2, Mgat1, F4/80, Mcp1 and Tnfα, which are involved in thermogenesis, lipogenesis and chronic inflammation in the liver and adipose tissues. Transfer of the FGF21 gene in HFD-induced obese mice greatly increased the expression of thermogenic genes in adipose tissue, resulting in similar improvements in systemic metabolism including reduction of adiposity, alleviation of fatty liver and attenuation of insulin resistance. Mechanistic studies on the effects of FGF21 gene transfer in lean mice revealed that mice transferred with FGF21 gene displayed suppressed lipogenesis in the liver and enhanced thermogenesis in brown adipose tissue which was coincident with a significant improvement in glucose tolerance. Collectively, our results suggest that transfer of the FGF21 gene could be considered a promising approach for treating obesity and its complications.

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Hydrodynamic delivery of FGF21 gene alleviates obesity and fatty liver in mice fed a high-fat diet

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