Leptin has not evolved as a therapeutic modality for the treatment of obesity due to the prevalence of leptin resistance in a majority of the obese population. Nevertheless, the molecular mechanisms of leptin resistance remain poorly understood. Here, we show that increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in the hypothalamus of obese mice inhibits leptin receptor signaling. The genetic imposition of reduced ER capacity in mice results in severe leptin resistance and leads to a significant augmentation of obesity on a high-fat diet. Moreover, we show that chemical chaperones, 4-phenyl butyric acid (PBA), and tauroursodeoxycholic acid (TUDCA), which have the ability to decrease ER stress, act as leptin-sensitizing agents. Taken together, our results may provide the basis for a novel treatment of obesity.