Lentiviral vector-mediated knockdown of Lrb in the arcuate nucleus promotes diet-induced obesity in rats

Abstract

Obesity is currently a worldwide pandemic. Leptin resistance is a main mechanism of obese human and rodents. The downregulation of the long form of the leptin receptor (Lrb) was involved in leptin resistance in diet-induced obese rats. In the studies, we investigated whether arcuate nucleus (ARC) silencing ofLrbwould promote diet-induced obesity in rats. Lentiviral vectors expressingLrb-shRNA were administered to 5-week-old male rats by ARC injection. Following viral delivery, the rats were provided with a high-fat diet (HFD) or a chow diet (CD). After 8 weeks of the diet, serum leptin, and insulin concentrations were measured by RIA, gene expression ofLrbin the ARC was detected by a real-time RT-PCR, and leptin signaling was examined by western blot. TheLrb-shRNA knocked down the expression ofLrbmRNA in infected regions by 54% for the HFD rats and 47% for the CD rats respectively. TheLrbknockdown reduced Stats3 activation and increased expression ofNpymRNA. The rats with reducedLrbin the ARC showed a significant increase in energy intake and body weight (BW) again when fed with a HFD. By contrast, there were no effects ofLrbreduction on energy intake or BW when rats maintained on a low-fat chow. Our results provide evidence thatLrbknockdown selectively in the ARC promotes diet-induced obesity and associated metabolic complications in rats.