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.