Leptin injections evoke weight loss by causing a reduction in food consumption and an increase in energy expenditure. Also, the administration of leptin lowers blood glucose levels in some rodent models of diabetes and in humans with lipodystrophy. We explored the therapeutic potential of delivering leptin to obese, diabetic ob/ob mice and to mice fed on a high-fat diet (HFD), by transplanting gut-derived cells engineered to produce leptin, under the regulation of an inducing agent, mifepristone. These cells expressed and released leptin in a mifepristone dose-dependent and time-dependent manner. The engineered cells were either transplanted into the mice under the kidney capsule or were encapsulated in alginate and injected into the intraperitoneal cavity, while mifepristone was delivered by implanting 14-day release pellets. In ob/ob mice, leptin delivery by this method caused a significant reduction in food intake and profound weight loss, which was controllable by adjusting the dose of mifepristone. These transplants also achieved rapid and persistent amelioration of diabetes. However, mice fed on a HFD were resistant to the leptin therapy. These results indicate that gut cells can be modified to express leptin in an inducible manner and that the transplantation of these cells has a therapeutic effect in leptin-deficient mice, but not in mice fed on a HFD.