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Treatment of obesity and diabetes by a regulatable leptin cell therapy system

University of British Columbia

Obesity, a chronic disorder that is increasing in prevalence worldwide, is a major risk factor for the development of type 2 diabetes, a metabolic disorder characterized by hyperglycemia. In this thesis, the efficacy of a leptin cell therapy was evaluated for the treatment of obesity and diabetes in leptin-deficient ob/ob mice and in high fat fed, leptin-resistant C57BL/6J mice. A gut endocrine K-cell line was engineered to produce leptin under the regulation of an RU486 controlled GeneSwitch™ system. In culture, these cells express and release leptin in an RU486 dose- and time-dependent manner. These cells were transplanted into ob/ob mice via (a) kidney capsule and (b) intraperitoneal (IP) injection of alginate encapsulated cells along with 14-day RU486 pellets. In mice that received leptin-producing cells under the kidney capsule, reductions in body weight (10%), food intake (50%) and blood glucose levels (67%) were observed 10 days post-transpjant, relative to controls. Body weight and food intake rapidly increased thereafter to that of controls. Interestingly, however, blood glucose concentrations remained reduced by 40% up to 2 weeks post-transplantation. Animals given IP encapsulated cells lost up to 17% of body weight and then rapidly returned to their starting weight 14 days later at exhaustion of the RU486. Remarkably, despite the fact that body weight was completely regained within 20 days posttransplantation, blood glucose concentrations remained reduced by almost 70% up to 50 days post-transplantation. Both the number of transplanted cells and the dose of RU486 given could regulate the effects of leptin cell therapy. Obese C57BL/6J mice on a high fat diet did not respond with reductions in body weight, food intake or blood glucose levels after being transplanted with encapsulated leptin-producing gut cells. These data demonstrate that leptin administered via a cell therapy strategy can result in a reduction in body weight, food intake and long term corrections of blood glucose concentrations in leptin sensitive ob/ob mice but not in high fat fed leptin resistant C57BL/6J mice under the conditions tested.

Text

2009-12-15

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http://hdl.handle.net/2429/16652

Physiology

University of British Columbia

UBCV

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