Metformin booster adipocyte-targeted gene therapy for the treatment of obesity and related metabolic syndromes

Obesity has become an important public problem that endangers human conditions and urgently needs to be solved. However, most weight-loss drugs on the market have little effect and are accompanied by adverse effects such as strokes and heart attacks. Here, we construct an adipocyte-targeting polypeptide-based gene carrier consisting of an adipocyte-targeting peptide and p-toluylsulfonyl arginine-modified polylysine (ATS-PLL-RT), which can specifically bind to the prohibitin of mature adipocytes. We further construct a short hairpin RNA (shRNA) to simultaneously silence fatty acid binding proteins 4 and 5 (shFABP4/5). FABPs are molecular chaperones for fatty acid metabolism and storage in cells. Moreover, we introduce metformin for combined therapy. First, the metformin combination can effectively improve the efficiency of gene transfection. In addition, metformin itself has an alleviating effect on diet-induced obesity and relevant metabolic diseases. The combination treatment of obese mice with ATS-PLL-RT/shFABP4/5 and metformin achieves body weight reduction and metabolic recovery. This study provides a potentially effective strategy for the clinical treatment of obesity as well as mitigating obesity-induced metabolic syndromes.