Treatment of Obesity Through Glial Cell-Derived Neurotrophic Factor Lipid Nanoparticle Delivery in Mice

Abstract

The overexpression of glial cell-derived neurotrophic factor (GDNF) in the liver and adipose tissues offers strong protection against high-fat diet (HFD)-induced obesity in mice. We hypothesize that sustainably enhancing GDNF expression in the liver may provide a therapeutic effect that can prevent the progression of HFD-induced obesity in mice. Expression lentivector encoding mouse GDNF (GDNF(pDNA) or empty vector (pDNA, control) were encapsulated in lipid nanoparticles (LNPs) using the thin-film hydration method. Mice were fed with regular diet (RD) or HFD for 20 weeks prior to injection and the GDNF and control vector-loaded LNPs were administered by intravenous (IV) injection to mice once weekly for 5 weeks. Changes in body weight were monitored and mice tissues were collected and imaged for fluorescence using an IVIS in vivo imaging system. Post-treatment abdominal fat weight, colon length, and spleen weight were obtained. GDNF protein levels in the liver and serum were quantified by enzyme-linked immunosorbent assay, while liver AKT serine/threonine kinase and AMP-activated protein kinase phosphorylation levels were evaluated by Western blotting. IV-injected GDNF(pDNA)-loaded LNPs targeted the liver and remained in there for up to 15 days postinjection. A single injection of GDNF(pDNA)-loaded LNPs significantly increased GDNF expression for 7 days and consequently increased the levels of phosphorylated AKT serine/threonine kinase and AMP-activated protein kinase. Once weekly injections of GDNF(pDNA)-loaded LNPs for 5 weeks slowed increase in body weight, reduced abdominal fat, and modulated the gut microbiota toward a healthier composition in HFD-fed mice. GDNF(pDNA)-loaded LNPs could potentially be developed as a therapeutic strategy to reverse weight gain in obese patients.