Treatment of Obesity and Diabetes in Mice by Transplant of Gut Cells Engineered to Produce Leptin

Abstract

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.

The prolonged survival of fibroblasts with forced lipid catabolism in visceral fat following encapsulation in alginate-poly-l-lysine

“…Previous attempts to reduce HF diet-induced obesity in mice by leptin-producing microcapsules failed due to the multifactorial nature of this metabolic disorder [2]. Remarkably, fat accumulation was reduced after transplantation of subcutaneous fat [13] and fibroblasts engineered with Prdm16 and C/EBPβ, leading to differentiation of these cells into Ucp1-positive thermocytes [9].…”

“…In mouse models, several genes playing a critical role in development of obesity have been identified [2,6]. Traditionally appetite-and energy expenditure- regulating hormones like leptin were considered for obesity treatment [2], but failed due to the development of leptin resistant conditions in rodents [24] and humans [25] with general obesity.…”

“…Traditionally appetite-and energy expenditure- regulating hormones like leptin were considered for obesity treatment [2], but failed due to the development of leptin resistant conditions in rodents [24] and humans [25] with general obesity. Microcapsules with gut K cells secreting leptin also showed promising results in leptin deficient ob/ob mice; however, the microcapsules lack a therapeutic effect on high-fat (HF) diet-induced obesity in wild-type C57Bl/6J (WT) [2]. Many genes regulating thermogenesis or thermocyte differentiation successfully offset obesity on regular diets consistent with their role in energy expenditure [9,26,27] in genetically-modified animals.…”

Leptin Production by Encapsulated Adipocytes Increases Brown Fat, Decreases Resistin, and Improves Glucose Intolerance in Obese Mice

“…In the absence of functioning leptin, the ob/ob mouse rapidly develops obesity and hyperglycemic conditions similar to T2DM [ 6 , 20 – 22 ]. Reintroduction of leptin by injection of exogenous recombinant leptin, adenovirus transduction restoring leptin expression in tissues, or transplantation of tissues producing leptin attenuate weight gain, improve glucose tolerance, decrease appetite, and increase metabolic rate in ob/ob mice [ 6 , 23 – 26 ]. However, these methods of leptin delivery cannot be directly translated into therapies for humans.…”

Reprogramming gut and pancreas endocrine cells to treat diabetes

“…Nonetheless, the mifepristone‐treated cell transplant group displayed transient hypoglycaemia, and the levels of plasma human insulin were not significantly different after a glucose gavage, a reflection of the generally poorly glucose responsiveness of tumour‐derived enteroendocrine cells. In another study, we used a similar approach to engineer GTC‐1 cells to produce human leptin [22], based on the therapeutic properties of leptin to reduce food intake, increase energy expenditure and improve glucose homeostasis. The K cell line was engineered so that leptin was produced and released in a mifepristone dose‐ and time‐dependent manner.…”