Liver-specific, non-viral gene delivery of fibroblast growth factor 21 protein expression in mice regulates body mass and white/brown fat respiration.

Viral-mediated in vivo gene delivery methods currently dominate among therapeutic strategies within the clinical and experimental settings, albeit with well-documented limitations arising from immunological constraints. In this study, we demonstrate the utility of non-viral hepatotropic in vivo gene delivery of unpackaged expression constructs, including one encoding fibroblast growth factor 21 (FGF21). FGF21 is an important hepatokine whose expression positively correlates with therapeutic outcomes across various animals models of obesity. Our data demonstrate that FGF21 expression can be restored into the livers of immunocompetent FGF21 knockout mice for at least two weeks after a single injection with an FGF21 expression plasmid. In wild-type C57BL6/J mice, in vivo transfection with an FGF21-expressing plasmid induced weight loss, decreased adiposity, and activated thermogenesis in white fat within two weeks. Furthermore, in vivo FGF21 gene delivery protected C57BL6/J mice against diet-induced obesity by decreasing adiposity and increasing uncoupling protein 1-depedent thermogenesis in brown fat, and by boosting respiratory capacity in subcutaneous and perigonadal white fat. Together, the data illustrate a facile and effective methodology for delivering prolonged protein expression specifically to the liver. We contend that this method will find utility in basic science research as a practical means to enhance in vivo studies characterizing liver protein function. We further believe our data provide a rationale for further exploring the potential clinical utility of non-viral gene therapy in mouse models of disease. Significance Statement This study presents a valuable method for non-viral gene delivery in mice that improves upon exisiting techniques. The data provide a rationale for further exploring the potential clinical utility of non-viral gene therapy in mouse models of disease, and will likely enhance in vivo studies characterizing liver protein function.